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(2019)Many drugs are associated with the risk of QT prolongation and torsades de pointes (TdP). The risk increases with other risks factors for QT prolongation. Recognizing risk factors and QT prolonging drugs is critical in the management of this drug-related problem. The aim of this master’s thesis was to study the prevalence of use of QT prolonging drugs in older adults receiving home care. Additionally, the aim was to study concomitant use of QT prolonging drugs as well as clinically significant QT prolonging drug-drug interactions in the participants. The secondary objective was to study the most commonly used QT prolonging in the participants. The material used in this master’s thesis originated from a randomized controlled trial in City of Lohja, Finland, which enhanced a coordination in medication risk management for older home care clients. The analysis of the baseline data collected in fall 2015 was only deepened regarding QT prolonging drugs. The participants (n=188) were older adults (≥65 years) receiving regular home care from City of Lohja, randomized into an intervention group (n=101) and a control group (n=87). The majority of the participants were women (69%). The mean age of the participants was 83 years. Data on the participants’ drugs were collected from their medication lists. Clinically significant drug-drug interactions were identified using the SFINX database. The QTDrugs Lists of CredibleMeds were used for identifying drugs associated with QT prolongation and TdP. On average, the participants (n=188) used 2.3 drugs (SD 1.3, median 2.0) associated with QT prolongation and TdP. Of the participants, 36% (n=67) used drugs with known risk of TdP (QTDrugs List 1). The most commonly used drugs with known risk of TdP were donepezil and citalopram. The prevalence of QTDrugs List 2 drugs (possible risk of TdP) was 36% (n=67). Most of the participants (n=156, 83%) used drugs which under certain circumstances are associated with TdP (QTDrugs List 3). One fifth (21%) of the participants used concomitantly 2-3 drugs associated with QT prolongation and TdP. QT prolonging drugdrug interactions (SFINX-D interactions) were found in 3% of the participants. The drugs involved in the drug-drug interactions were donepezil, (es)citalopram and haloperidol. The prevalence of use of clinically relevant QT prolonging drugs (QTDrugs Lists 1-2) was higher in this study compared with the prevalence in outpatients in previous studies. Concomitant use of QT prolonging drugs is common in outpatients. Health care professionals need to be educated on the risks of QT prolongation, TdP and the risks of using QT prolonging drugs concomitantly. Risk assessment tools considering patient-specific risk factors could be more widely used, as they may reduce modifiable risk factors, and actual events of QT prolongation and TdP may be avoided. There is a need for systematic procedures for assessing and managing the risks of QT prolongation and TdP in the Finnish health care system.
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(2019)Pharmaceutical industry is supervised by several competent authorities. These authorities all over the world inspect manufacturers in order to make sure they comply with the Good Manufacturing Practice (GMP) guidelines and produce quality products. If non-compliance with the guidelines is detected, the authorities can revoke manufacturing licenses and deny access of the products. Recent trend in pharmaceutical industry is that the Active Pharmaceutical Ingredient (API) manufacturing is concentrated in few factories. If this kind of manufacturer is declared non-compliant and is therefore unable to supply an API, it can lead to drug shortages. This research aimed to find out what kind of quality problems occur in API manufacturing. Because of the concentration trend, it is important to understand what kind of problems the manufacturers do struggle with to prevent any risk for shortages. This research aimed also to determine how much the quality problems in API manufacturing can impact on drug shortages. Also, the number and location of these non-compliance cases were investigated. The chosen time frame was 2016-2018. Several databases were used as information sources in this research. These databases are maintained by the authorities in the U.S. and Europe and they contain information about the inspections and the GMP deficiencies they have found during these inspections. With the information collected from the databases, an inductive content analysis was conducted to determine the reasons for non-compliance with GMP in API manufacturing. Other information (e.g. locations, names of APIs) was also collected from the databases and analysed to answer the rest of the research questions. Results show that the biggest problem areas in API manufacturing were data integrity and analytical testing. Other problems relating to documentation occurred also. The amount of these cases was quite stable, and the relative proportion declined during the time period. Comparison between the list of APIs and drug shortage databases showed that even over 30% of the non-compliant APIs were later in shortage. The effect was greater in Finland than in the U.S. Therefore, it was concluded that the most significant GMP deficiencies in API manufacturing were poor data integrity and inappropriate analytical testing procedures. Secondly, the number of non-compliance cases in API manufacturing has not increased during this time, but these problems may have had an impact on drug availability problems.
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(2023)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.
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(2022)Native nanofibrillated cellulose is wood-derived, animal-free biocompatible biomaterial which has proved the suitability of nanoscale cellulose fiber based hydrogels for 3D cell culturing and wound healing applications. The problem of freeze-drying nanofibrillated cellulose hydrogel (NFCh) has been the aggregation of the hydrophilic fibrils of the NFC during freeze-drying, which leads deformed freeze-dried cake and unsuccessful reconstitution of the sample. Molecular Dynamic (MD) simulations have been earlier applied in formulation design of NFCh for freeze-drying successfully by screening excipients based on their attraction to the surface of NFCh. The weakness of MD simulations is it can only model the fresh formulation system intend to freeze-dry, but not the actual freeze-drying process and the effect of it and the excipients to the material. To evaluate the protecting properties of excipients and therefore the accuracy of the MD simulations detailed information about changes in the physical state and molecular orientation of the formulation before and after freeze-drying is needed. Non-invasive and label-free Raman spectroscopy can be used to determine vibrational modes of molecules to investigate changes in molecular orientation of the material. The aim of this study was to investigate the possible molecular changes induced by freeze-drying of NFCh-based formulations utilizing Raman spectroscopy and evaluate the connection of the results to MD simulations. NFCh with different excipients was freeze-dried and physicochemical properties, rheology and Raman signal were measured before and after freeze-drying and compared to the literature of MD simulations. The principal component analysis (PCA) was done to the Raman spectra and differences evaluated. The spectra of all formulations differed before and after freeze-drying, and more detailed analysis was done to two most potential 0.8% NFCh based formulations, lactose 300 mM and lactose 250 mM + glycine 50 mM. They had great attraction to NFCh in MD simulations and very similar rheological properties before and after freeze-drying and reconstitution. The spectra of different state of both formulations different on areas between 400 - 500 cm-1 and 850 - 900 cm-1 based on PCA analysis contributing the mutarotation of lactose during freeze-drying and reconstitution. Freeze-drying and the absence of water molecules in NFCh formulation favor different ratios of β and α anomers than the fresh hydrated state which could be detected utilizing Raman spectroscopy. Therefore, Raman spectroscopy was confirmed to be a sensitive option to assess subtle changes in molecular orientation in fresh, freeze-dried, and reconstituted NFCh-based formulations, resulting in a detail knowledge of the molecular behavior of excipients which could be applied in MD simulations and design of better freeze-drying formulations in future.
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(2024)Light-sensitive liposomes have gained attention for their ability to deliver cargo to tissues, offering spatiotemporal control over drug release. Red-light wavelengths have been utilized as an external trigger in light-sensitive reactive oxygen species (ROS)-mediated drug delivery, due to their favorable properties, such as the low light absorption by tissue chromophores. The ROS-sensitive drug delivery systems use photosensitizers (PS), which upon light exposure generate ROS in the presence of molecular oxygen. Palladium(II)phthalocyanine (Pd(II)PC), a new second-generation photosensitizer, can upon light irradiation generate relatively high singlet oxygen concentrations, enabling the efficient oxidation of the unsaturated lipids. The oxidation of the lipids leads to the disruption of the liposome bilayer and eventually, the release of the encapsulated cargo. To gain deeper insight on the phthalocyanine-labeled liposomes in drug delivery, a red light-triggered cationic liposome formulation encapsulating Pd(II)PC was formulated. The characteristics of the liposomes, the release mechanisms, and the release quantities of calcein (623 Da) and fluorescent-conjugated dextrans (4 000-70 000 Da) were studied following red-light exposer with 630 nm, 450 mW/cm2 laser while utilizing varying Pd(II)PC-loading quantities. Following oxygen removal and temperature-induced release studies, the mechanism of release of the liposomes was principally observed to be light-triggered reactive oxygen species-mediated. In the light-induced release studies an effective release of the calcein, and a relatively effective release of the Rhodamine B dextrans (10 kDa, 70 kDa) were observed from the liposomes via the Pd(II)PC-generated and reactive oxygen species-mediated oxidation of the unsaturated lipids. The release of the biomacromolecules from the liposomes was observed to require longer irradiation times than that of calcein. The longer irradiation times likely lead to deeper oxidation of the unsaturated phospholipids, resulting in a comprehensive eruption of the liposome bilayer. The comprehensive eruption of the liposome bilayer eventually enables the sufficient release of biomacromolecules from the liposomes.
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(2016)Adverse drug events (ADE) are a major problem which deteriorates the quality of drug therapy. They cause significant morbidity and mortality each year. ADEs are often caused by incompatible drug combinations, drug-drug interactions (DDIs). Interprosessional collaboration between health care professionals is important in improving medication safety and preventig drug interactions. The aim of this study was to investigate the most common clinically significant drug-drug interactions in outpatient care and the role of pharmacist in preventing them. The study material was an interaction data which was collected in Helsinki University Pharmacy during August 2015. DDIs and the action needed by presecribers or pharmacists to handle them were collected. Only clinically significant interactions of the SFINX interaction database i.e. D- and C-interactions were recorded. The most common D-interactions (interactions to be avoided) were fluoroquinolones or tetracyclines combined with metal ions (calcium, iron, magnesium, aluminium) (14.7 % of D-interactions) and codeine or tramadol combined with CYP2D6 enzyme inhibiting antidepressants (12.6 %). C-interactions concerned most commonly interactions between antihypertensive drugs and NSAIDs (26.2 % of C-interactions). 59.6 % of D-interactions were interactions that might result in adverse drug reactions and 40.4 % were interactions that might result in therapeutic failure. For C-interactions numbers were 49.4 % and 50.6 %, respectively. Only a few interactions (1.6 %) led to contact with the prescriber from the pharmacy, and more often (1.8 %) the pharmacist advised the patient to contact the prescriber. 32.6 % of the interactions led to pharmacist's advice. The most typical interactions which can be prevented by pharmacist's advice were chelation interactions which can be prevented by taking drugs many hours apart from each other. 59.7 % of the interactions produced no action in pharmacy. Those concerned situations where the prescriber had planned the treatment and weighed up the benefits and risks of the medication, or interactions where the drugs had been in contemporary use for a long time, and thus the pharmacist assumed that the prescriber had planned the treatment. Pharmacists should intervene in drug-drug interactions easier. To avoid unnecessary calls, communication between prescribers and community pharmacies should be developed. Pharmacists' role in preventing DDIs could be improved for example by education and by updating the operations models in collaboration with other health care. Safe and efficient drug treatment should be ensured with interprofessional collaboration, and the responsibility should not be shifted to the patient alone.
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(2021)Biologisten lääkkeiden tarjonta ja käyttö ovat lisääntyneet voimakkaasti viimeisen vuosikymmenen aikana. Biologiset lääkkeet voivat parantaa reumasairauksien ja useiden muiden pitkäaikaissairauksien hoitotuloksia. Biologiset lääkkeet ovat yleensä perinteisiä pienimolekyylisiä lääkkeitä kalliimpia, ja siksi biologisen alkuperäislääkkeen kanssa kliinisesti samanarvoiseksi kehitettyjen edullisempien biosimilaarien käyttöä pyritään edistämään osana rationaalista lääkehoitoa. Potilaan näkemyksillä ja niiden huomioimisella on hoitoon sitoutumisen ja hoidon tulosten kannalta suuri merkitys. Potilaiden näkemyksistä ja kokemuksista biologisista lääkkeistä ja niiden vaihdosta on melko vähän tutkimuksia. Tutkimuksen tavoitteena oli tutkia reumapotilaiden tietämystä ja näkemyksiä biologisista lääkkeistä ja biosimilaareista sekä kokemuksia niiden ei-lääketieteellisestä lääkevaihdosta. Lisäksi tutkittiin reumapotilaiden uskomuksia omasta lääkityksestään, halukkuutta osallistua lääkitykseen liittyvään päätöksentekoon lääkärin kanssa ja biologisten reumalääkkeiden käyttäjien lääketiedon lähteitä. Tutkimus toteutettiin sähköisenä kyselynä Yliopiston Apteekin kanta-asiakkaille ja kertomalla siitä Reumaliiton ja IBD- ja muut suolistosairaudet ry:n viestinnässä 18.–30.1.2021. Kohderyhmänä olivat aikuiset avoterveydenhuollon reuma-, IBD- ja muut suolistosairaus-, sekä ihopsoriasispotilaat, jotka käyttivät adalimumabin tai etanerseptin alkuperäistä biologista lääkettä (BA) tai biosimilaaria (BS) tai ainoastaan perinteisiä pienimolekyylisiä lääkeitä (PL). Tässä tutkimuksessa tarkasteltiin vastauksia 260 reumapotilaalta, joista biologisia lääkkeitä oli käyttänyt 75 (BA-käyttäjiä 35, BS-käyttäjiä 40) ja perinteisiä lääkkeitä 185. Ei-lääketieteellisen lääkevaihdon kokeneita oli 17. Tutkimuksen teoreettisena viitekehyksenä käytettiin terveysuskomusmallia. Ensisijaiset lopputulosmuuttujat olivat faktorianalyysillä muodostettuja summamuuttujia. Erot lääkekäyttäjäryhmien (BA, BS, PL) välillä ja taustamuuttujien vaikutukset testattiin tilastollisilla analyyseillä. Vastanneista potilaista 94 % tunnisti biologisen lääkkeen käsitteen, mutta biosimilaari-käsite tunnettiin huonommin (34 %). Suurin osa potilaista (73–78 %) luotti biosimilaarien olevan ominaisuuksiltaan samankaltaisia alkuperäisvalmisteiden kanssa. Lääkärin tekemään biologisten lääkkeiden vaihtoon luotettiin enemmän (89 %) kuin mahdollisesti apteekissa tehtävään vaihtoon (40 %). Tutkimuksessa todetut kokemukset biologisten lääkkeiden vaihdosta biosimilaariin olivat pääosin positiivisia. Tutkimuksen reumapotilailla oli hyvä tietämys biologisista lääkkeistä, mutta he tunsivat huonommin biosimilaarin käsitteen ja mitä biosimilaarit ovat. Heillä oli yleisesti ottaen luottavainen näkemys siitä, että biosimilaari on ominaisuuksiltaan alkuperäisvalmistetta vastaava lääke. Biologisten ei-lääketieteelliseen vaihtoon suhtauduttiin melko myönteisesti, mutta lääkärin toteuttamaan lääkevaihtoon suhtauduttiin luottavaisemmin kuin mahdollisesti apteekeissa tehtävään vaihtoon. Lisää tutkimustietoa tarvitaan muun muassa potilaiden biosimilaareihin kohdistuvan epävarmuuden syistä.
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(2014)Reverse-phase protein microarray, RPMA, is a novel and promising technology for proteomic profiling. The low sample consumption, high-throughput format, high sensitivity and good precision make RPMA attractive tool for clinical use. In RPMA, cellular lysates obtained from various sources (e.g. clinical samples, cell lines) are arrayed onto a substratum as a small spots such that an array is comprised of hundreds to thousands of different samples. The array is incubated with a capture molecule (e.g. antibody) that is validated to recognize the analyte of interest. Signal is created by labelled secondary antibody and the signal is detected by colorimetry, chemiluminescence or fluorescence methods. The literature part introduces the RPMA technology and its applications. RPMA have been utilized in versatile applications for example in cell signal pathway profiling, drug discovery and discovery and validation of biomarkers. In the future, it is hoped to allow individual therapy regimes and the evaluation of treatment efficacy. The aim of the experimental part was to culture various cell lines and prepare lysates for RPMA. The lysates were prepared of ARPE-19, HepG2, Hepa-RG, SKOV-3-ip1, SKOV-3, Caco-2, hCMEC/D3, HCE and D-407 cell cultures. The lysates were stored in -80 °C for subsequent use in RPMAs. The purpose was to optimize the method and based on the optimization studies, to print one RPMA. Cell lysates were arrayed onto nitrocellulose coated glass slide using Nano-Plotter (Gesim)-device which allows automated sample printing. β-actin and α-tubulin proteins were assessed from the samples. To create the signal, fluorescence dye was used, and detected at the visible wavelengths. Based on this study, more optimization is required. The detection method used in the RPMA was not optimal, but the experiment showed promising potential. By taking into account the development issues, the method performance can be significantly improved. Of these issues, perhaps the most important is to use infrared region for the signal detection instead of visible wavelengths.
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(2014)Ricinus communis L., also known as castor, is a worldwide cultivated plant. Castor seeds are a source of castor oil, an important ingredient in industry. Castor seeds also include one of the most toxic natural compounds - ricin toxin. Ricin toxin has medical purposes, but it can be abused. There is fear that it will be used as a biological weapon or with terrorism. Ricin is listed as a forbidden chemical on Chemical Weapons Convention, CWC. Ricinus is regarded as a monotypic genus, but there is strong variability in its characters. This study concentrates on the taxonomical classification of the Ricinus varieties. Here is represented a taxonomical description of following varieties: "AGF-6", "AGF-M", 'Blue Giant', 'Cambodgensis', 'Carmencita Bright Red', 'Gibsonii', 'Green Giant', 'Impala', 'New Zealand Purple', 'Sanguineus', var. zanzibarensis (mixed), and 'Zanzi Palm'. Also an identification key for varieties is shown. This study is made for VERIFIN (Finnish Institute for Verification of the Chemical Weapons Convention). If the chemical composition especially with the amount of ricin toxin correlates with the morphological characters, the taxonomical classification can provide an important identification tool. This way the monitoring of chemical weapons can be facilitated.
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(2011)River blindness (onchocerciasis) is a human helminth disease that is caused by Onchocerca volvulus filaria. It is endemic in tropical areas in Africa and Latin America. About 37 million people are infected. River blindness manifests in cutaneous and eye symptoms that are caused by the youngest forms (microfilariae). Against river blindness there has been mass drug treatments with ivermectin which has an effect on microfilariae. There is a need for a drug that kills adults or sterilizes females. A vaccine would be even better. Antibiotics are a new treatment because O. volvulus has Wolbachia bacterium as an obligate symbiont. Doxycycline kills at least 60 per cent of adults and sterilizes females. But the course lasts many weeks. A promising compound is emodepside that has a new mechanism of action for an anthelmintic drug. Numerous compounds has been examined to get drugs for filarial diseases. Some of them inhibit enzymes with which filariae evade human immune defence. Others disturb moulting that takes place four times. A good target for a drug is essential for the parasite but absent from mammals. Betulin is a triterpene that is abundant in birch bark. Betulin and many of its derivatives are pharmacologically active compounds that are examined particularly as cancer and HIV drugs. The research group of medicinal chemistry in University of Helsinki has synthesized and examined many derivatives. Some of them are promising for example against Leishmania protozoans, Chlamydia pneumoniae bacterium and alphaviruses. That is why those compounds should be tested against other causes of diseases like filariae. Both Wolbachia and C. pneumoniae have the same lipid biosynthesis pathway that is essential for both. Heterocycloadducts between betulin and nitrogen heterocycle were synthesized whose alcohols were oxidized to carbonyls. In both Leishmania donovani and L. braziliensis examinations the most effective compound was heterocycloadduct of formylbetulin. Although the compounds have not been examined against filariae, in future it would be worth an effort to synthesize derivatives that has nitrogen instead of carbonyls because the compound effective on C. pneumoniae is dioxime.
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(2019)Breast cancer is the most common cancer among women world wide and it´s incidence is constantly growing. The prognosis of local breast cancer is good and patients with metastatic breast cancer are living longer with their disease. The growing survivorship and population of chronically ill breast cancer patients has made quality of life one of the most important aspects in the treatment of breast cancer. Cytotoxic chemotherapy is a widely used treatment for breast cancer. Chemotherapy can cause difficult adverse events, which can affect the patients’ quality of life. Chemotherapy can also relieve the symptoms caused by cancer when used to treat metastatic breast cancer. The aim of this systematic review was to collect the currently available literature about breast cancer patients´ health related quality of life as comprehensively as possible, review the quality of the literature and the effects of chemotherapy on breast cancer patients ‘quality of life. The literature search produced 1666 references. According to the inclusion and exclusion criteria, 107 full text articles were accepted to the final systematic review, 53 of which reported the health related quality of life during adjuvant treatment of breast cancer, and 51 of which reported it during the treatment of advanced or metastatic breast cancer. In addition 3 previous systematic reviews were found. The basic information about the articles was extracted into a table. Articles were heterogeneous regarding their study settings, used quality of life instruments and reporting. Most studies used a disease specific quality of life instrument. The collected literature gave a strong indication of quality of life worsening during adjuvant chemotherapy of breast cancer. This observation was further supported by the previous systematic reviews. Most of the studies reporting the quality of life during chemotherapy for metastatic breast cancer, reported less than clinically important changes during the treatment. A few studies reported clinically important worsening or improvement in quality of life. 11 studies, which were made during or after 21: st century, which reported numerical data from quality of life, which reported predominantly quality of life and which had sample size of at least 100 patients in baseline, were accepted to further assessment of quality of the studies and closer observation. The quality of the studies was assessed with STROBE and CONSORT checklists. The quality of studies was heterogeneous as the studies fulfilled 44.8 % to 86.1 % of the scoring items. Only one randomized controlled trial reported quality of life as their primary end point. The data from these studies supported the previous observation of quality of life worsening during adjuvant chemotherapy of breast cancer. The effect of chemotherapy during metastatic breast cancer on quality of life was not unambiguous. Both clinically meaningful worsening and improvement of quality of life was reported. Breast cancer patients´ health related quality of life has been assessed in multiple publications, but the existing literature is heterogeneous and it´s use in decision making and economic evaluation is not easily feasible. Breast cancer patients´ health related quality of life worsened during adjuvant chemotherapy. Significant improvement in breast cancer patients´ health related quality of life was not observed during chemotherapy for metastatic breast cancer.
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(2018)Breast cancer is the most common cancer in women worldwide and the number of new events is on the increase. Like many other serious diseases, breast cancer reduces patient’s health related quality of life (HRQoL) and breast cancer treatment burdens our society. Examination of breast cancer patient’s HRQoL makes it possible to calculate how effective breast cancer treatments are. Nevertheless, only cost-effectiveness analysis would further help us allocate the resources of our society in the best way possible. The aim of this study was to produce research about breast cancer treatment’s effects on patient’s HRQoL and to compare generic 15D- and EQ-5D-5L-instruments. The results can be used in the future research and the study might be useful, when it’s time to develop international protocol for measuring HRQoL. The study population included 152 breast cancer patients who were treated in HUCH and whose HRQoL were measured by 15D-, EQ-5D-5L- and VAS-instruments. All measurements were done twice, first before the treatments and then six months after the beginning of the treatments. 89 (58.6 %) patients answered both 15D-questionnaires and 81 (53.3 %) patients answered to both EQ-5D-questionnaires. 57 (37.5 %) patients didn’t respond to any questionnaire. Only some background information was available of this population. The average HRQoL for breast cancer patients’ was 0.92 before the treatments and 0.88 six months after the beginning of the treatments when measured by 15D. The same average HRQoL was 0.86 before the treatments and 0.80 six months after the beginning of the treatments when measured by EQ-5D-5L. During six months’ period, patients HRQoL reduced (-0.04) when it was measured by 15D and (-0.06) when it was measured by EQ-5D. The changes of HRQoL were clinically important (The minimum important change, MIC > ± 0,015) when measured by 15D. HRQoL reduced more with patients who received a mastectomy than with patients, who received a breast conserving surgery according to both instruments. According to the results, the chosen instrument has an effect of breast cancer patients’ HRQoL. It means that the chosen instrument also has an effect of treatment’s effectiveness. 15D offers higher HRQoL values, but EQ-5D offers a greater change in patient’s HRQoL. HRQoL was measured by two different generic instruments in two different times, which was assumed to be the strength of this study. The new 5L-version of EQ-5D-instrument was also used. This is possibly the first time, when 5L is used in this type of study.
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(2017)Atrial fibrillation is the most common sustained cardiac arythmia. It has been estimated that there will be 14 to 17 million atrial fibrillation patients in Europe by the year 2030. In Finland, there are over 50 000 atrial fibrillation patients. The prevalence of atrial fibrillation increases by age. In addition to age, people who have hearth failure, high blood pressure, coronary artery disease, valvular hearth disease, diabetes mellitus, chronic kidney disease or who suffer from obesity have increased prevalence. Atrial fibrillation is usually not a life threatening condition. However, people who suffer from atrial fibrillation have a greater risk of the stroke compared with people who have normal sinus rhythm. Warfarin has been the standard treatment for preventing the stroke in atrial fibrillation patients. However, there are many inconveniences in warfarin therapy such as food and drug interactions and frequent laboratory visits. Therefore, new oral anticoagulants have been introduced to prevent the stroke in non-valvular atrial fibrillation. These new drugs apixaban, dabigatran, edoxaban and rivaroxaban are more expensive than warfarin. Many people suffer from atrial fibrillation and the number of atrial fibrillation patients is increasing. Due to the expected increase in the number of atrial fibrillation patients in future the costs of the new drugs have led to a concern for their impact on the health care budget. The knowledge of the cost-effectiveness of the new anticoagulants is important for decision making. In this Master's thesis, the cost-effectiveness of rivaroxaban was compared with warfarin for stroke prevention in non-valvular atrial fibrillation. Systematic literature review was used as the study method and 363 studies were screened and 23 of them filled the inclusion criteria. One was a previously published systematic review and 22 were cost-utility studies. All of the cost-utility studies had used decision analytic modelling. The studies were conducted in 13 different countries. In the cost-utility studies included in this systematic review there was a great variability in the cost-effectiveness of rivaroxaban compared with warfarin. Rivaroxaban was cost-effective in more than half of the studies, for example in Belgium, Italy, Norway and Singapore. However, in China, Thailand and Slovenia the cost-effectiveness could not be established. Contradictory cost-effectiveness results were obtained in studies conducted in Germany, Canada and USA. The incremental cost-effectiveness ratio varied from 2580 € to 174915 € per quality adjusted life years (QALY) gained with warfarin over all the 22 cost-utility studies. In studies conducted in Europe the incremental cost effectiveness ratio varied from 4188 € 139163 €/QALY gained. In studies where rivaroxaban, apixaban, dabigatran and warfarin were compared together using an indirect comparison or a network meta-analysis it seemed that rivaroxaban was not the optimal treatment. The most common adverse effect of anticoagulation treatment is bleeding. This complication was included in all the cost-utility studies. However, there was only some uniformity of the bleeding events reported. In most cost-utility studies the acute care cost of intracranial hemorrhages was reported and in many studies, also the long term costs. The cost-utility studies included in this systematic review were quite heterogeneous. Because they were done in different countries their health care settings, treatment options and costs were different. There were also differences in cost-effective models. Modell structure, settings, data and assumptions were different. Due to the heterogeneous nature of the studies, no unambiguous answer could be reached to the question concerning the cost-effectiveness of rivaroxaban compared with warfarin. The quality assessment of the cost-utility studies revealed that some quality criteria were not met. Transferability of the results from one country to the other seemed to be poor. The strength of this master's thesis is the comprehensive literature search concerning the cost-effectiveness of rivaroxaban compared with warfarin. Also, the reporting of methods and results are transparent. There are also limitations in this study. One person was conducting the literature search, data extraction and quality assessment. This might have increased the risk for subjective interpretations and errors.
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Ruokahalun säätely ja lihavuuden lääkehoito : lihavuuslääkkeiden tehoseulontamenetelmä seeprakalalla (2014)Obesity is a significant problem for public health. Obesity develops when systems controlling food intake and consumption are imbalanced. Many different brain areas and transmitters contribute to maintain energy balance. Signals that are secreted proportional to body's fat storage (leptin and insulin) regulate energy balance in a long run. Hormones that are secreted from gastrointestinal tract control food intake in a short run. These hormones are for example cholecystokinin, peptide YY and ghrelin. Drug treatment for obesity is limited because effective drugs are lacking. The only drug to treat obesity in Europe is orlistat but it's effectiveness is modest. The development for new antiobesity drugs has been busy. Problems in drug development have however delayed drugs in the market. The aim of this study was to develop a method with which we could measure how much food zebrafish (Danio rerio) has been eaten and to study how different drugs affect feeding behavior of the zebrafish. The purpose was also to do high throughput screening of antiobesity drug with this method and to study how genes affect feeding. The amount of food that zebrafish ate was able to be measured by utilizing fluorescent rotifers as fish's food. Drugs that are known to affect feeding (fluoxetine and rimonabant) reduced the amount of food zebrafish ate when measurement was done in 6-well plate and with two hours feeding. Sibutramine did not affect food intake, although it has been shown to reduce food intake in zebrafish in another study. The effect of gene knock down was also studied with morpholino oligonucleotides. MANF, th2 or galanin gene knock down did not affect food intake in zebrafish. The conclusion is that the new method is well suited for food intake measurements and drug effectiveness studies. The method can not be used in high throughput screening because results can not be analyzed by a plate reader and the feeding can not be done in 96-well plate.
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(2014)Parkinson's disease is a progressive neurodegenerative disease. The incidence of the disease is 1.5-2 per cent after age 60. Typical symptoms are tremor, rigidity and bradykinesia. At the late stage of the disease patients have psychic disorders, for example dementia, anxiety and depression. Motor impairment is caused by degenerative loss of dopamine cells in nigrostriatal tract. Current treatment of the disease relieves the symptoms but it cannot stop or slow the progress of the disease. Neurotrophic factors and gene therapy have been trialled to improve the treatment of Parkinson's disease and the results have been encouraging. Neurotrophic factors are proteins that regulate actions of neurons. It has been discovered that they are neuroprotective and neurorestorative. The results with glial cell line-derived neurotrophic factor (GDNF) have been encouraging in in vivo studies of Parkinson's disease. There has been variability in success of clinical trials though. GDNF degrades quickly in vivo but overexpression of GDNF in cells can be produced with viral vector adeno-associated virus. Two different forms of GDNF, pre-α-pro-GDNF (α-GDNF) and pre-β-pro-GDNF (β-GDNF), are produced as precursors and they are activated proteolytically. Based on in vitro studies, some differences in secretion of precursors have been discovered. α-GDNF is secreted constitutively and secretion of β-GDNF is dependent on physiological stimulation. Previous in vitro studies have focused on α-GDNF, but β-GDNF might be a better solution for treating Parkinson's disease based on physiological regulation system. Cerebral dopamine neurotrophic factor (CDNF) is recently discovered and less studied than GDNF. It has been discovered that CDNF also has neuroprotective and neurorestorative effects in animal models of Parkinson's disease. The aim of the first part of this study was to discover the neurorestorative effect of single injection of CDNF injected above substantia nigra for rats that received injection of 6-hydroxydopamine (6-OHDA) into medial forebrain bundle. One week later rats received PBS, GDNF or CDNF injection. The degree of the lesion was estimated with apomorphine (0.1 mg/kg s.c.) or d-amphetamine sulphate (2.5 mg/kg) induced rotation test. The rats were perfused nine weeks post-lesion and their brains were sliced. Tyrosine hydroxylase (TH) positive dopamine cells were stained by immunohistochemistry. The amount of TH positive cells in substantia nigra was counted and optical density of TH positive fibres in striatum was measured. The aim of the second part of the study was to research the neuroprotective effect of two different precursors of GDNF, dsAAV1-pre-α-pro-GDNF and dsAAV1-pre-β-pro-GDNF, given with viral vectors. The dopamine cells in nigrostriatal tract were destroyed with a 6-OHDA injection into striatum and viral vectors were injected two weeks later. Rats in control group received injection of dsAAV1-GFP. The degree of the lesion was evaluated with d-amphetamine sulphate (2.5 mg/kg) induced rotation tests and cylinder test. The rats were perfused eight weeks post-lesion and their brains were processed for immunohistochemistry. The results of the study were interesting and supporting previous studies. The success of the neurotrophic factor treatment is dependent on a successful injection of protein or viral vector, and the dose is dependent on the size of the lesion. Neurotrophic factors and gene therapy needs to be studied more before wide clinical usage.
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(2012)ommunity pharmacies and medicines information centers increasingly provide e-mail medication counseling services to consumers and health care professionals. As e-mail medication counseling services are fairly new type of pharmaceutical service, only little is known about the use and users of these services, content of e-mail enquiries and quality of these services. Objective of this study was to analyze utilization of e-mail medication counseling services in the University Pharmacy. The special focus was on e-mail enquiries concerning human and veterinary medicines and health issues. All e-mail enquiries sent to the University Pharmacy Medicines Information Center in 2009 and 2010 were recorded by using a structured data collection instrument and content-analyzed both qualitatively and quantitatively. The total numbers of e-mail enquiries were 3 376. Of those 383 (11 %) were related to human medicines, 45 (1 %) to health and diseases and 33 (1 %) veterinary medicines. The majority of e-mail enquiries (72 %) were come via web page of the University Pharmacy. Of the human medicines related e-mail enquiries 92 % were sent by consumers and 65 % by woman. The most commonly e-mail enquiries concerned sleeping pills (5 %), antiepileptics (3 %), cholesterol medicines (3 %) and virus vaccines (3 %). E-mail enquiries fell commonly into the categories of availability (28 %), cost and reimbursements questions (13 %), medicines interactions (11 %) and adverse effects (5 %). Some background information was missing from e-mail enquiries, for example user of medicine (39 %), gender of medicine user (50 %) or age of medicine user (94 %). However, only part (3 %) of e-mail enquiries were sent adjunct questions. After improvement of usability and quality of e-mail medication counseling services response rapidity was increased in the University Pharmacy. Consumers appear to have medicines-related information needs. Additionally they are actively using e-mail services for multiple functions. However, the use of these services for medicines information is still fairly uncommon. The results of this study can be utilized when designing and developing e-mail medication counseling services in community pharmacies, medicines information centers and online pharmacy services. Additionally they can be utilized in pharmacy education in universities and in continuing education. More information is needed about the quality of pharmacists' responses and consumers' needs, experiences and perceptions on e-mail medication counseling services.
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(2019)Pitkäaikaiset lääkitykset lisääntyvät jatkuvasti kroonisten sairauksien yleistymisen ja väestön ikääntymisen takia. Pitkäaikaisten sairauksien hoidossa lääkehoitojen rationaalisuus korostuu, mutta WHO:n arvioiden mukaan noin puolet lääkkeiden määräämisestä, toimittamisesta, käytöstä ja myynnistä toteutuu epärationaalisesti. Tämä lisää terveydenhuollon ammattilaisten vastuuta lääkehoidon vaikutusten seurannassa ja potilaan hoitoon sitouttamisessa myös reseptien uudistamisessa. Reseptien uudistamiskäytäntöjä on kuitenkin tutkittu vähän niin Suomessa kuin maailmanlaajuisesti. Tässä pro gradu -tutkielmassa tavoitteena oli tarkastella nykyisiä reseptien uudistamiskäytäntöjä perusterveydenhuollon lääkäreiden näkökulmasta. Tavoitteena oli tarkastella, minkälaiset tekijät vaikuttavat lääkäreiden työskentelyyn sekä potilaan lääkehoidon kokonaisuuden hallintaan ja turvallisuuteen reseptien uudistamistilanteissa. Lisäksi kartoitettiin lääkäreiden ratkaisuehdotuksia uudistamiskäytäntöjen kehittämiseksi. Tutkimus toteutettiin laadullisena monimenetelmätutkimuksena Kirkkonummen terveysasemilla. Tutkimuksessa hyödynnettiin triangulaatiota ja tutkimusaineisto koostui reseptien uudistamistilanteiden varjostuksesta sekä kahdesta lääkäreiden ryhmähaastattelusta. Tutkimukseen osallistui yhteensä 12 lääkäriä, joista viisi osallistui varjostusvaiheeseen ja seitsemän haastatteluvaiheeseen. Aineisto kerättiin huhti-heinäkuun 2019 aikana. Tutkimuksen teoreettisena viitekehyksenä oli inhimillisen erehdyksen teoriaan perustuva järjestelmälähtöinen näkökulma. Tutkimusaineisto analysoitiin aineistolähtöisellä sisällönanalyysillä, jossa varjostus- ja haastatteluaineistosta etsittiin tutkimuksen tavoitteiden kannalta merkittäviä ilmaisuja. Reseptien uudistaminen on lääkäreiden näkökulmasta monivaiheinen prosessi. Prosessiin vaikuttivat useat uudistamista helpottavat ja vaikeuttavat järjestelmä-, potilas- ja lääkelähtöiset tekijät. Lääkärit tunnistivat ongelmakohtia uudistamisprosessin jokaisesta vaiheesta. Lääkäreiden mukaan etenkin tietojärjestelmien epäkäytännölliset ominaisuudet ja tekniset ongelmat sekä ajantasaisten lääkitystietojen ja tiedonkulun puutteet olivat uudistamistilanteissa ongelmallisia ja tekivät uudistamisesta työlästä. Myös kiire ja uudistettavien reseptien suuri määrä vaikeuttivat uudistamista. Ongelmien takia lääkärit kokivat, ettei lääkehoitojen seurantaa voitu tehdä uudistamistilanteessa perusteellisesti. Lääkäreiden ehdotuksia uudistamisprosessin kehittämiseen olivat uudistamisen parempi koordinointi, tietojärjestelmien ja tiedonvälityksen kehittäminen sekä moniammatillisen yhteistyön ja potilaan osallistamisen lisääminen.
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(2009)Stakes ja Lääkehoidon kehittämiskeskus määrittelevät lääkitysturvallisuuden lääkkeiden käyttöön liittyväksi turvallisuudeksi, joka voi vaarantua missä tahansa lääkehoidon vaiheessa. Yksi lääkitysturvallisuuteen vaikuttava lääkehoidon osa-alue on lääkeneuvonta. Koska lääkkeitä käytetään ammattilaisilta saatujen ohjeiden perusteella, on lääkeneuvonnan kehittäminen tärkeää. Lääketietouden lisäämisen ohella lääkeneuvonnalla voidaan vaikuttaa lääkkeiden käyttäjien asenteisiin. Lapsen lääkitykseen kohdistuva lääkeneuvonta on haasteellista, sillä huomio täytyy kiinnittää sekä lapseen että vanhempiin. Tutkimuksessa selvitettiin sairaalasta kotiutettavan lapsipotilaan lääkeneuvonnan sisältöä ja kehitystarpeita sekä lääkeneuvonnan toteuttamiseen vaikuttavia asioita. Lisäksi tutkimuksen avulla selvitettiin vanhemmille kotiutuksen jälkeen ongelmallisia lääkehoitoon liittyviä asioita. Tutkimusaineistona käytettiin HUS:n Lastenklinikalla työskentelevien sairaanhoitajien teemahaastatteluja. Toisena aineistona käytettiin vanhempien osastolle soittamia, lasten kotiutuksen jälkeistä lääkehoitoa koskevia puheluita. Aineiston keräys tapahtui hoitajien avulla heidän kirjatessaan tarkoitusta varten muodostettuun lomakkeeseen ylös ne lääkehoitoa koskevat kysymykset, joita vanhemmat soittavat osastoille kotiutuksen jälkeen. Keräykseen osallistuivat HUS:n infektio-osaston, lastentautien osaston ja munuais- ja elinsiirto-osaston hoitajat. Syyskuun 2009 aikana suoritettuihin teemahaastatteluihin osallistui 10 infektio-osaston sairaanhoitajaa. Kuten aiemmissakin tutkimuksissa on todettu, sairaanhoitajilla on suuri vastuu sairaalassa annettavasta lääkeneuvonnasta. Tutkimustulosten mukaan sairaanhoitajat pyrkivät kattavaan lääkeneuvontaan. He painottavat erityisesti perheen pärjäämistä kotona havainnollistamalla antamaansa neuvontaa kirjallisen materiaalin ja antotekniikkaan liittyvän opetuksen avulla, sekä kiinnittämällä huomiota perheen asenteisiin lääkehoitoa kohtaan. Esteinä lääkeneuvonnan toteuttamiselle koettiin sekä vanhempien että hoitajien kiire, joidenkin vanhempien vääränlainen asenne, hoitajien ja vanhempien kielimuurista johtuvat kommunikaatio-ongelmat, neuvontatilan rauhattomuus sekä hoitajille suunnattujen yhteisten ohjeistuksien puute. Lääkeneuvontaan liittyviksi kehityskohteiksi nousivat sekä vanhemmille että hoitajille suunnatut kirjalliset ohjeet, lääkkeisiin liittyvä lisäkoulutus, neuvonnan ajoitus, neuvontatila ja osastofarmaseutin osallistuminen neuvontaan. Kahden kuukauden tutkimusjakson aikana loka-marraskuussa 2009 kirjattiin osastoilla yhteensä 26 kotiutetun potilaan lääkehoitoa koskenutta puhelua. Infektio-osastolle tulleet yhteydenotot (n=7) koskivat pääasiassa lääkkeen annosteluaikoja ja kuurin tarkkaa kestoa. Yksi puhelu koski haittavaikutuksen ilmaantumista ja yksi antotekniikkaa. Lastentautien osastolle tulleista puheluista (n=11) kymmenen koski insuliinien annostusten muuttamista verensokeriarvojen korjaamiseksi. Munuais- ja elinsiirto-osastolle vanhemmat soittivat yleensä kysyäkseen annosteluun liittyviä erityisasioita, kuten annostelua oksennuksen, väärän lääkkeenantoajan ja yliannoksen jälkeen.Munuais- ja elinsiirto-osastolla puheluita kirjattiin yhteensä kahdeksan. Tutkimuksen mukaan hoitajien antama lääkeneuvonta on perusteellista. Lääkehoitoon liittyviä asioita jää kuitenkin vanhemmille epäselväksi, vaikka huomiota kiinnitetään niihin asioihin, joissa vanhemmat tarvitsevat eniten tukea. Osastoille kehitetyn lääkeneuvontamallin tarkoitus on auttaa hoitajia lääkeneuvonnan toteutuksessa, mutta huomionarvoista olisi myös osastofarmaseutin mahdollisuus osallistua neuvontatilanteeseen. Jatkotutkimuksissa olisi hyvä selvittää, millä tavalla neuvontamallia hyödynnetään neuvonnan toteuttamisessa. Erityisesti lapsille suunnattua lääkeneuvontaa on kehitettävä.
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(2013)Hospital pharmacies and drug centers are responsible for pharmaceutical services for inpatient care in the public health care in Finland. Each of the 20 hospital districts have a central hospital pharmacy. Every hospital district is a member of one of the five regional hospital groups (called erva-alue). In each regional hospital group the area's university hospital is responsible for the specialized hospital care. Most of the regional hospital groups cooperate in drug purchasing. The drug purchasing policies need to be in line with the legislation regulating public sector's purchasing policies. Usually procurement and organizing a tender competition are coordinated by university hospitals. With centralization hospital pharmacies can get cost-benefits. This study deals with drug purchasing policies in hospitals and regional hospital group cooperation in Finland. The objective was to explore drug purchasing process in hospital pharmacies and related cooperation in regional groups. The study was carried out as a postal survey which was sent to the head pharmacists of all 20 hospital districts in spring 2012. The survey instrument was reviewed by selected experts and revised according to their comments before it was sent to the respondents. Most of the questions were open-ended enabling the respondents to reflect their opinions. The response rate was 90% (n=18). All respondents answered to the most of the questions. There were seven procurement groups. Most of the regional cooperation groups procured drugs together. Only Helsinki University Hospital's (HYKS) regional cooperation group did not procure and organize a tender competition together. Purchasing period was generally two years. Usually procurement was centralized to the university hospitals in the regional groups. The hospital pharmacies that had two years purchasing periods reasoned the duration of the period most commonly by cost savings. The pharmacies that had a three-year or longer period explained its length by drug safety. The areas also differed in the way they involved specialists in selecting pharmaceutical products and making final decisions. The expertise of the specialists involved varied widely. Some areas involved a very broad range of experts, while some others had few. The drugs were selected independently by or within groups. Procurement criteria varied a lot, but the main criterion in all the responses was price or total cost-effectiveness. The respondents reported that drug safety was considered in the procurement but its inclusion as a purchasing criterion was challenging. Few of the respondents reported having studied cost savings of using purchasing groups. However, cost savings were believed to be significant. Particularly, the respondents reported that workloads had decreased because of the cooperation in procurement. Some changes were reported to happen in the drug procurement processes of some purchasing groups. All these ideas concerning drug purchasing policies and cooperation are described in the research report. For example, some head pharmacists indicated their willingness to have national cooperation in establishing drug guidelines. Most of them were satisfied with the current cooperation and purchasing policies and were ready to continue and develop the cooperation. The study achieved its goal in exploring drug purchasing policies and cooperation between hospitals in Finland. The study can perform as a baseline evaluation for further studies in the field. It also provides useful information to those people working on drug procurement and purchasing policies.
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(2020)Salvinorin A is a dissociative hallucinogen found in the plant Salvia divinorum. Unlike other hallucinogens it is a selective kappa-opioid receptor antagonist with no affinity to serotonin receptor 5-HT-2A. Modern case studies suggest low, regularly used salvinorin A doses might have antidepressant properties. In animal studies salvinorin A causes both pro- and antidepressant behaviour. Other hallucinogens, such as classical psychedelics psilocybin and LSD, show great promise as rapid acting antidepressants in multiple clinical trials focusing on treatment resistant depression. The most well-known rapid acting antidepressant drug ketamine belongs to the same group of dissociative hallucinogens as Salvinorin A. The use of subanesthetic ketamine has become an integral part of treatment resistant patient care in Finnish healthcare. Ketamine as well as chronic treatment with traditional antidepressants induce plasticity via BDNF-TrkB signaling. The antidepressant mechanism of classical psychedelics is mostly unknown, but they have been shown to promote neuroplasticity by increasing the expression of immediate-early genes and spinogenesis in cortical neurons. The experimental part of this master’s thesis examines the acute effects of salvinorin A on the signaling pathways associated with antidepressant response in C57BL/6 mice. To better characterize the effects of salvinorin A an open field test of 100 min was carried out in addition to phosphorylation studies. Single high dose (5-10 mg/kg) of salvinorin A causes a robust reduction in locomotor activity almost immediately after i.p. administration in mice. However it does not affect the phosphorylation of proteins associated with antidepressant response, nor does it affect BDNF m:RNA expression in mouse prefrontal cortex. According to previous studies, the therapeutic effects of salvinorin A might be present only at low doses or in regular microdosing.
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