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Nonadherence has been a challenge in health care since ancient times, and it is still a major source of poor therapeutic outcomes today. Various theories and theoretical models have been applied to explain adherence. So far no single theory or theoretical model has proved comprehensive, and the effects of various interventions applied have been limited. Theorizing of adherence is still incomplete. The aim of this study was to review the theoretical background of adherence so far, and to find the commonalities in theories and theoretical models, but also to discover possible trends in them. Study material comprised 20 theories and theoretical models. Material was found in reference books and documents with an aspect of adherence. Inclusion criteria involved adult outpatients with chronic diseases, excluding any special groups such as pregnant women. Emphasis was on the relevance of the theory, but comprehensive time span as well as various theory views were also considered. A chronological order was created. A qualitative content analysis was conducted, where phrases describing essential theory contents were categorised into distinctive classes. The incidence of classes and the possible trends of the incidence were analysed. Five classes emerged as commonalities in majority of the theories: Patient factors; sociocultural factors; motivation; phrases that referred to a behavioral view; and cognitive processes. Factors that diminished towards this day were the pivotality of cognitive processes in theory, and the subjective view of the health threat. Several factors were found to increase towards present-day theories and models: phrases that described the individual’s agency, such as self-efficacy or empowerment, concrete expressions of the individual’s abilities, skills and actual opportunity to the desired behavior, phrases that consisted of behavior being a function of its context or environment, and phrases where multifaceted intervention or tailoring the intervention according to the change process phase were considered. The commonalities found in the material reflect its emphasis on psychological behavior theories. The changes reflect the shift in how the patient’s agency is viewed in a patient care relationship. Newer theories also amplify the importance of viewing health behavior change as a series of phases. To achieve patient-centered care, these aspects create an increasing demand to health care professionals’ proficiency in how they encounter their patients. Moreover, there is an important signal for future intervention development in the form of a shift into multifaceted interventions and a system approach. Furthermore, a trend exists from using more general and abstract theories to a more concrete and applied approach. In the future, it is probably more fruitful to pursue knowledge-based and validated models and guidelines that are applicable to practice instead of aiming at developing a comprehensive universal theoretical approach.

Indomethacin is in a BCS-classification class two drug, meaning it has poor solubility but good permeability. Because of this solubility is a limiting factor for it reaching bloodcirculation. Amorphous form has better solubility than crystalline form. Most common problems with amorphous form are poor stability and process technical problems. In this study Indomethacin was combined with two different kind of polymers that were prepared by hot-melt extrusion. By hot-melt extrusion we can get more stable product than pure amorphous drug. These polymers were polyvinylpyrrolidone (PVPK179 and polyvinylpyrrolidonevinylacetate (PVPVA). They were prepared with Indomethacin 1:1 mass ratio. The aim was to study these extrudates and their stability, cumulative release and especially permeability. By using differential scanning calorimetry, X-ray diffraction and polarized light microscopy it was possible to analyze whether the drug was amorphous or crystalline. In the study it was found that by using hot-melt extrusion it was possible to make amorphous combinations of Indomethacin and polymers. Their permeability was between crystalline and amorphous form. PVPK17-Indomethacin combination had better permeability than PVPVA-Indomethacin combination. On the other hand PVPVA-Indomethacin had better cumulative release than PVPK17-Indomethacin combination

Current treatments for major depressive disorder have notable limitations including the delay achieving the therapeutic effect. Ketamine has been shown to alleviate the symptoms of depression rapidly and promising findings have also been found when using nitrous oxide. However, the mechanisms behind rapid antidepressant effect are not fully discovered. It seems that rapid-acting treatments alter brain energy metabolism, enhance synaptic plasticity, and repair neuronal dysfunction connected to depression. Particularly, the activation of brain derived neurotrophic factor (BDNF) mediated tropomyosin receptor kinase B (TrkB) signaling has been connected to rapid antidepressant effect. Fasting is also known to induce BDNF production and it is thought to activate BDNF-TrkB signaling. In addition, both of these treatments alter the brain energy metabolism. The objective of this study was to find out how fasting and nitrous oxide alone and in combination affect the rapid antidepressant effect and synaptic plasticity related BDNF-TrkB signaling in mice. Another aim of the research was to determine whether the body temperature changes after these treatments as a marker of metabolic rate. The analyzed brain samples of the mice were collected 15 minutes after cessation of nitrous oxide administration. As a result, it was found that the fasting protocol used in this study did not activate the studied BDNF-TrkB signaling. However, after nitrous oxide administration, the studied signaling and markers related to synaptic plasticity were partly activated. The results from the combination of nitrous oxide and fasting were similar compared to nitrous oxide administration only. It is therefore conceivable, that the effects were caused exclusively by nitrous oxide. Furthermore, a fascinating finding related to energy metabolism was that nitrous oxide reduced the body temperature of the mice significantly 15 minutes after cessation of the gas administration. Overall, these results are promising and consistent with previous research indicating that nitrous oxide administration could be related to induced synaptic plasticity and therefore have antidepressant associated effects. Nitrous oxide could be used to understand the mechanisms behind rapid antidepressant effect and it could be a potential option to treat depression in the future. Based on these results, it seems that energy metabolism could be related to rapid antidepressant effect. It also supports the observations that all different rapid-acting treatments alter the brain energy metabolism.

Angiogenesis, the formation of new blood vessels from preexisting vascular network, is an essential process during tumor development. Growing tumors secrete different growth factors that induce angiogenesis, of which vascular endothelial growth factor (VEGF) is predominant. Angiogenesis inhibitors act either by blocking the extracellular bindning of growth factor to its receptor by monoclonal antibodies or by blocking the intracellular signalling pathway by small-molecule agents. The small-molecule agent sunitinib is a multitargeted tyrosine kinase inhibitor that has antiangiogenic and antitumor activities due to the selective inhibition of several tyrosine kinase receptors. Sunitinib is approved for treatment of gastrointestinal stromal tumors, renal cell carcinoma and pancreatic neuroendocrine tumors. Known side effects are hypertension, cardiotoxicity and renal damage. These toxic effects are due to sunitinibs "off-target" toxicity, which occurs when a tyrosine kinase inhibitor causes adverse effects via inhibiton of a kinase not intended to be a target of the drug. For example inhibition by sunitinib of AMPK, a kinase that plays key roles in maintaining metabolic homeostasis in the heart, accounts in part for the toxicity seen in cardiomyocytes exposed to sunitinib. By achieving a better understandning of what causes the side effects it could be possible to develop treatments that reduce off-target effects. Caloric restriction is one nonpharmacological approach that has been shown to have beneficial effects on the heart partly by activating sirtuins. Sirtuins regulate a diverse array of cellular functions, including metabolism, gene transcription, cell division and cellular stress response. The aim for this study was to investigate whether caloric restriction improves sunitinib-induced cardiovascular toxicity and renal damage in rats, and to study activated cellular pathways. In this study 40 spontaneously hypertensive rats (SHR) and 10 normotensive Wistar-Kyoto (WKY) rats were used. They were divided into groups depending on treatment; I WKY control, II SHR control, III SHR + caloric restriction 70 %, IV SHR + sunitinib 3 mg/kg and V SHR sunitinib 3 mg/kg + caloric restriction 70 %. The follow-up period was eigth weeks. Blood pressure was messured weekly, metabolic cages were used week 4 and week 8 for urine samples, echocardiography was performed the last week and vascular response was studied at the end. The proteins Sirt1 and AMPK in heart were investigated by Western blot and the amount of the marker of macrofage ED1 in kidney by immunohistochemistry. Based on this study it was observed that the dose 3 mg/kg sunitinib was well tolerated in rats because it did not cause more extensive hypertension, worse hypertrophy or renal damage compared to untreated SHR groups. This study also showed that short-term caloric restriction has beneficial cardiovascular effects.

The background of this study is increase in the ageing population and in medication use. Aged-related changes in pharmacodynamics and pharmacokinetics may change medication response in elderly patients and lead to adverse reactions. For elderly people the risk of being hospitalized due to adverse drug reactions is four times higher than for younger people. Many of these problems could be prevented by avoiding the use of certain drugs in the elderly. Several criteria have been developed to assess medication appropriateness in the elderly. The aim of this study was to develop a new Finnish Medication Risk Assessment (MRA) tool to be used by trained nurses to assess the presence of risks related to use of medicines in outpatients aged 65 years and older. A preliminary tool was developed through a comprehensive literature review of tools to indicate appropriateness and risks of elderly medications, and through expert opinions. The tool was then validated by using three-round Delphi-method. Delphi-method is a qualitative consensus method which is based on group judgement of a subject matter. The first and the second Delphi-rounds measured the tool's suitability and the third Delphi-round measured the importance of the items of the tool in estimating risks related to the use of medications of elderly patients. In this study, 33 expert geriatric panelists were approached of whom 11 physicians, three pharmacists MSc (Pharm.) and four nurses agreed to participate. The results from the Delphi-rounds were evaluated both quantitatively and qualitatively. Through the three-round Delphi-method was developed a MRA -tool that contains 19 items. According to the panelists the items of the tool are either important or moderately important. This indicates that the tool is valid to estimating medication risks in use of medications in this population. Further studies are needed to test the tool among nurses and patients. The MRA -tool was primary developed for estimating risks in medication use, but it could also be used for educational purposes. In the future, it is possible to implement safer and more appropriate pharmaceutical treatment for elderly patients by using this Medication Risk Assessment -tool.

The medicines information and counseling given by health care professionals are essential in supporting patients' medication therapy. Given that medication therapies are often associated with medicine-related problems among the elderly, proper knowledge on medicines and their use is especially important for this particular patient group. Benzodiazepines and related drugs are of special concern in the elderly. Despite the current care guidelines, they are commonly used by the elderly, often also regularly and long-term basis. Benzodiazepines and related drugs are associated with multiple potential adverse drug reactions that their elderly users should be aware of. This study aimed at assessing the knowledge on medications, and needs and sources of medicines information on benzodiazepines and related drugs in the elderly. Especially, medicines information related to benefits and adverse drug reactions was studied. Additionally, data on use and subjective experiences of benzodiazepines or related drugs in the elderly were explored. Structured interviews were conducted among patients aged 65 years and using benzodiazepines or related drugs (n = 38) in acute wards (n = 2) of Pori City Hospital in 2004. Elderly patients reported that the package leaflet was the main source of medicines information on benefits and adverse drug reactions relating to medicines they used. The physician was reported as a second source after the package leaflet. More than 50 percent of the elderly (n = 20) had not received information about the benefits or adverse drug reactions of benzodiazepines from their health care providers or relatives. The information received had merely focused on benefits of drug than adverse drug reactions. Most commonly the elderly (61 %, n = 23) knew, that the use of benzodiazepines can cause drug dependence. Least commonly, they were aware that benzodiazepines can cause muscular weakness, depression and falling over. Eight elderly were not aware of any asked adverse drug reactions and nearly two thirds of the patients (63 %, n = 24) knew less than four adverse drug reactions out of eleven. The results indicate that elderly patients are not well aware of the effects of benzodiazepines and related drugs they use. Additionally, they may more often receive information from the package leaflet than health care professionals. Physicians and other health care professionals should pay more attention to counseling elderly patients especially about the benefits and adverse drug reactions of benzodiazepines and related drugs.

Current therapies for depression have limitations in efficacy and delayed onset of action. Rapid-acting antidepressants like ketamine, an N-methyl-D-aspartate receptor (NMDA-R) antagonist, have gathered attention as an improved treatment option. However, the neurobiological mechanism underlying their antidepressant effect remains uncertain. Integral mechanisms of action seem to be alterations in synaptic plasticity, global cortical excitation, and repair of neuronal dysfunctions prevalent in the pathophysiology of depression. Emerging evidence does suggest that antidepressant drugs act by facilitating brain derived neurotrophic factor (BDNF) mediated tropomyosin receptor kinase B (TrkB) signaling. Interestingly, rapid-acting antidepressants seem to increase TrkB-associated signaling after their acute pharmacological effect has dissipated, and when animals become sedated and show various physiological changes associated with deep sleep (e.g., slow wave EEG activity, SWA). Indeed, recently a close relationship between sedation and molecular signaling implicated in antidepressant effects has been discovered. The aim of this study was to explore the relationship between sedation and molecular signaling associated with antidepressant effect. This was carried out by assessing the localization of TrkB-associated phosphorylation signaling in the adult male mice medial prefrontal cortex (mPFC) using dexmedetomidine, a sedative. Key signaling molecules such as ribosomal protein S6 kinase (p70S6K), ribosomal protein S6 (rpS6), glycogen synthase kinase 3 (GSK3), mitogen activated protein kinases (MAPKs) and immediate early gene c-Fos, were examined through immunohistochemical (IHC) analysis. Two separate experiments were conducted using naïve adult 8-13-week-old (n=8 and n=10) male C57BL/6JRccHs mice. In the experiments mice were injected intraperitoneally with either dexmedetomidine (0,05 mg/kg, Dexdomitor®), or saline followed by a 30-minute recovery period whereafter mice were euthanized. In the first experiment, medial prefrontal cortex samples were collected immediately post decapitation for western blot (WB) analysis. The results showed that dexmedetomidine significantly activated TrkB-associated signaling in brain homogenates, consistent with expectations. In the second experiment, mice were perfused with 4% paraformaldehyde (PFA) before brain collection for IHC analysis. However in this experimental setting, no significant difference in the localization of TrkB-associated signaling induced by dexmedetomidine was observed compared to saline. Although, no significant results for signal localization were observed, the results provide insights into the neurobiological effect of sedation induced TrkB-signaling. Further research factoring in limitations is needed to uncover the involvement of physiological states in antidepressant mechanisms.

Organic Anion Transporting Polypeptide 2B1 (OATP2B1) is an influx transporter expressed widely throughout the body in tissues such as intestine, liver, brain, placenta and skeletal muscle. Since many clinically used drugs are transported by OATP2B1, changes in the function of the transporter due to genetic polymorphism could lead to altered pharmacokinetics or -dynamics of OATP2B1 substrate drugs. The aim of this Master’s thesis was to create and optimize a cellular uptake assay to study the function of OATP2B1. Furthermore, the aim was to study the effects of six naturally occurring nonsynonymous single nucleotide variants on OATP2B1 transport function in vitro. With site-directed mutagenesis, single nucleotide changes were introduced into the gene coding for OATP2B1. OATP2B1 variants were expressed in human derived HEK293 cell line using baculovirus expression system. A cellular uptake assay with estrone-3-sulfate and a fluorescent probe 4’, 5’-dibromofluorescein (DBF) as substrates was set up and optimized. With the assay, OATP2B1-mediated uptake of variants was compared to the transport activity of OATP2B1 wild type. Amino acid changes Ser486Phe and Cys520Ser impaired OATP2B1 transport function severely. In addition, variant Thr318Ile transported DBF and estrone-3-sulfate less efficiently compared to OATP2B1 wild type, but Arg312Gln, Thr392Ile and Ser532Arg transport function was not affected. A method to study OATP2B1 function was created successfully. According to the results, single amino acid changes in OATP2B1 can impair OATP2B1 function. The results and method can be utilized to understand findings from pharmacogenetic studies in vivo, and to predict consequences of especially rare variants, which can be difficult to detect in small sample populations in clinical studies. However, further studies on the expression level and cellular localization of OATP2B1 variants are needed to fully characterize the impact of the variants studied.

Twin screw granulation (TSG) has gained considerable interest as a continuous wet granulation method in the pharmaceutical industry and has been studied the most. However, there is still lack of understanding how continuous granulation affects the material compaction behavior even though it has been noticed in several dry and batch wet granulation studies that the granulation process has an influence on the final tablet strength. Thus, studies on the material compactability and tabletability after continuous wet granulation are relevant for the overall understanding of twin screw granulation process and its effect on material behavior in tableting. Hence, the main objective of this study was to investigate the influence of continuous twin screw granulation on the compactability and tabletability of commonly used excipients. Additionally, the impact of binder on the compaction behavior of materials was examined. Furthermore, the suitability of two "loss in compressibility" models i.e. the Unified Compaction Curve (UCC) model and a porosity model to predict the loss in tablet strength after twin screw granulation and for the materials used was assessed. Earlier, the models have been applied to dry and batch wet granulations only. Full factorial design of three variables (binder type, binder addition method and the number of kneading elements) with two levels was conducted for the ConsiGma1 twin screw granulation of formulations containing microcrystalline cellulose (MCC), mannitol or anhydrous dicalcium phosphate (DCPA) as the main excipient and polyvinylpyrrolidone (PVP) or hydroxypropyl cellulose (HPC) as binder. Magnesium stearate was added as lubricant after granulation prior to tableting. In addition to the full factorial design, granulation with PVP, dry binder addition and four kneading elements was repeated for each main excipient. In total this made 27 experiments. The granules were dried and milled after granulation and all the batches were tableted. Additionally, all the formulations were direct compressed in order to be able to detect the change in compactability and tabletability after granulation. Torque of the granulation was determined as well as bulk density and particle size distribution of the granules. Additionally, the tensile strength and porosity of the tablets were analysed. Tabletability and compactability were determined based on the compaction pressure and the obtained tensile strength and porosity values of the tablets. Furthermore, parameters (PWG, TWG and εWG) describing the loss in compressibility models were calculated. MCC experienced loss in compactability and tabletability after twin screw granulation due to hornification effect. On the other hand, the compaction behavior of mannitol improved due to the formation of porous granules. The compactability of DCPA decreased and the tabletability increased. However, the change was only moderate presumably due to brittle nature of DCPA. Additionally, the binder type had an effect of the compaction behavior of the materials, PVP producing stronger tablets compared with the less hydrophilic HPC. However, the binder addition method played only a small role in modifying the compaction behavior. The UCC model was applicable to MCC as loss in tabletability was detected. Thus, the model can be used to predict tablet tensile strength when MCC is granulated with twin screw granulator. Additionally, the UCC model can be used to design the granulation process to achieve a target tensile strength based on small scale preliminary studies thus reducing the resources needed for case-studies. However, the UCC model was not feasible to mannitol and DCPA because they experienced improvement in tabletability after twin screw granulation. The porosity model was applicable to MCC and DCPA but not to mannitol as it showed improvement in compactability. The porosity model described the loss in compactability of MCC only moderately due to lack of tensile strength data points and the linearity of the tensile strength-porosity relationship. However, the model described well the loss in compactability of DCPA at tablet porosities achieved with compaction pressures used in industry. As a conclusion, the results demonstrate that twin screw granulation can have a significant impact on the final tablet strength and that the compaction behavior of the formulation can change either way depending on the used materials. Furthermore, the small influence of the binder addition method on the tablet strength indicates that the time consuming binder dissolving process step can be excluded from the tablet production chain enabling continuous manufacturing with twin screw granulation.

The aim of this master`s thesis was to investigate the accuracy of in silico inhalation model to predict pharmacokinetics of orally inhaled products. In literature review special features of the inhalation medication and current statements of medicinal regulatory agencies about bioequivalence (BE) of inhaled products are discussed. The ability of generalized pharmacokinetic BE studies to replace the traditional efficacy studies is a major question in the regulatory agencies. Also the usefulness of published in vitro - in vivo correlations (IVIVC) as an aid for inhaled product development in pharmaceutical industry is considered. Furthermore the most commonly used in silico lung deposition models and their properties are presented. In the experimental part a generic in silico inhalation model was constructed using a proper software and Orion Oyj`s in vitro and in vivo research materials on certain dry powder inhaler (DPI) products. Based on in vitro knowledge the aim of modeling was to predict the pharmacokinetic behavior of a therapeutic drug used in inhaled products. Also the applicability as a tool in clinical study design of inhaled products was estimated. Inhalation model consisted of two separate modeling parts utilizing primary in vitro characterization results of DPI products. Lung deposition of products was predicted with the ARLA (The Aerosol Research Laboratory of Alberta) respiratory deposition calculator available to the public while drugspecific pharmacokinetics was simulated using constructed Stella model (isee systems). ARLA lung deposition model takes into account several factors affecting the final lung dose of medical aerosol. Those include aerosol formulation and the dimensions of the device, as well as breathing conditions and inhalation mode. A rough sensitivity analysis was carried out with ARLA considering the effect of these factors on predicted lung deposition fractions. The predicted plasma concentration profiles, Cmax and AUCt values of the model drug were markedly lower than the experimental values. ARLA deposition model predicted moderately the order of systemic drug exposure obtained with different DPI products. The inhalation model built in the experimental part needs to be refined using more comprehensive and trustable source and reference material. The role of clinical BE studies in the marketing approval of generic inhalation product will be important because currently in silico predictions are still under development.