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(2016)Medication safety meaning the safety of using medication is an important part of patient safety. Medication errors are the most common preventable threats of patient safety. Medication errors can occur in all stages of the medication process. Rather than blaming individuals involved in the process, incidents should be evaluated based on system thinking with an aim of identifying system and process-based weaknesses allowing errors to happen. James Reason's human error theory provides a good framework to investigate the topic from this perspective. The objective of this study was to gather information on the medication errors based on the Patient Insurance Centre 2013-2014 data of compensated medication errors. One of the aims was to identify different types of medication errors and gather information on their backgrounds and drugs involved. Another aim was to investigate the causes behind the medication errors and the views of the people involved on the contributin factors of these errors. Additionally the study aimed at identifying situations where interprofessional collaboration could have prevented medication errors from occurring. Finally the results of the study were also compared with the results of the earlier studies done using similar data. The data of the study consisted of 205 cases where medication error had caused compensated patient injury. Factors behind the errors were analyzed using descriptive statistics. The examples of most common cases were investigated more in depth through simplified root-cause analysis. Content analyses were used to gather information on the views of the people involved in errors as well as on the possibilities of preventing errors through interprofessional collaboration. The most frequent error type was omission of medication. The majority of the errors occurred in the early stages of the process when decisions on medication and treatment were done. There were altogether 250 drugs in the data out of which 98 different active ingredients were identified. Antithrombotic agents were the most common therapeutic group causing medication errors. 37% of all drugs included in data were classified as high alert medicines. More efficient use of the interprofessional collaboration could have prevented several medication errors. The number of medication errors had somewhat increased compared to earlier studies but the profiles of errors were very similar. The data of Patient Insurance Centre provides valuable information on medication errors across Finland. More accurate information on factors leading to medication errors could be obtained by improving voluntary nationwide reporting. This would make it easier to develop operating models that improve patient safety.
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(2023)Physiologically based pharmacokinetic modelling (PBPK) can be used to predict pharmacokinetic behaviour of new drug molecules in human. PBPK model represents the body anatomically and physiologically with compartments connected to each other and combines those to drug specific parameters. PBPK modelling can be used to predict the absorption, disposition, and time-concentration profiles of drug molecules. The purpose of the study was to build a PBPK model for new drug molecule under research (compound A) and predict pharmacokinetics in human, to support the selection of dosing interval, formulation, and sampling time points for the first clinical trial. In this work it is described the building of the model in the ”bottom-up”-approach using in vitro parameters in GastroPlusTM-software. The modelling was done also for preclinical species (mouse, rat, dog) comparing the simulations to the observed in vivo data, which gave the confidence to the methods used in the modelling also for human. The model was first built for systemic kinetics and thereafter it was used for predicting pharmacokinetics after oral dosing. Parameters of systemic kinetics were compared also to the predictions from allometric scaling. Based on the preclinical species the most predictive method for the volume of distribution of compound A was the method by Lukacova, which predicted the volume of distribution to be moderate in human (1.7 l/kg). From the in vitro-to-in vivo -extrapolation methods the most predictive method to predict the clearance was the method by Poulin, which predicted low clearance in human (8.1-14.3 l/h). Empirical scaling factors based on the preclinical data were not needed, as the models predicted well the observed in vivo data. Allometric methods predicted the systemic kinetic parameters to be in the similar range. Advanced compartmental absorption transit -model (ACAT) integrated to GastroPlusTM-software predicted the absorption after oral dosing well in the preclinical species (predicted/observed ratio 0.8-1.3 for systemic exposure) despite the low solubility of the compound A. The model predicted the absorption in human to be sensitive to particle size and absorption rate to be clearly affected by the particle size. The feeding status was also predicted to affect on the absorption with larger particle sizes. The gut metabolism was not predicted to limit the oral exposure notably, whereas moderate bioavailability was predicted to be achievable. Compound A could be given in a capsule if the target particle size distribution could be achieved. The built PBPK-model can be used in the future to predict the first clinical doses by comparing the predicted plasma concentrations to in vitro pharmacodynamic parameters and to the plasma concentrations needed for efficacy in the pharmacodynamic models. The model can also be used to predict the drug-drug interactions.
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(2016)Suspension is nowadays the most commonly used dosage form in preclinical animal studies. However, suspension can be physically unstable and changes in particle size or crystal form of an active pharmaceutical ingredient (API) can occur during storage. Conventionally suspensions are also prepared in a mortar, and hence the quality of suspensions is operator-dependent. One of the aims in this study was to prepare suspensions using a mortar and pestle and an Ultra-turrax homogenizer to find out how the preparation method affects the particle size of suspension. A solution containing methylcellulose and Tween 80 was used as a vehicle, and five active APIs with different physico-chemical properties as model drugs. Moreover, an aim of the study was to evaluate the stability of the suspensions stored at room temperature and in the refrigerator and freezer by physical (laser diffraction, optical microscopy, X-ray powder diffraction) and chemical (high-performance liquid chromatography) methods of analysis. The aim of the study was also to assess and compare the suitability of laser diffraction and optical microscopy for the determination of partice size during preclinical studies. The suspensions prepared using a mortar and pestle and Ultra-turrax had a similar particle size in almost all cases. The particle size of API that was difficult to grind decreased significantly, also when using Ultra-turrax although the capacity used was minimum. Both prepation methods had the best repeatability of particle size when the API was easy to grind. However, Ultra-turrax could provide better homogeneity of quality than a mortar and pestle if the settings were optimized. The effect of different operators was not studied in this study. The stability of suspensions in different storage conditions was dependent on the properties of API. The particle size of all frozen suspensions decreased after two days based on laser diffraction results. Although the reason was not found from literature or supplementary tests (particle size analysis of the vehicle and pH-measurements), freezing of suspensions should be treated with caution based on this study. The crystal structures of APIs remained stabile with the exception of typical disproportionation of the API salt. Suspensions were mainly chemically stabile in all conditions, but water-solubility of API seemed to decrease stability. The micellar solubilization of drugs was also observed. The best way to determine the particle size of preclinical suspensions proved to be the combination of laser diffraction and optical microscopy images. The microscopy images confirmed the validity of the size distributions measured by laser diffraction and provided information about e.g. particle aggregation. On the other hand, optical microscopy image analysis was not suitable method for particle sizing.
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(2022)Traditional 2D cell cultivating vessels and experimental models cannot often simulate natural chemical and physical environment of different cell types. For example, availability of oxygen, chemical gradients, messaging molecules, fluid pressure, flow and surface topography are factors that may affect significantly in cell differentiation, growth, cellular structure, and metabolism. Modular bioreactors like Quasi-Vivo® -system can be used to simulate these factors. Liposomes are particles of phospholipid bilayer with aqueous space enclosed within. They can be modified in numerous ways, like loading them with hydrophobic and hydrophilic molecules, changing their transition temperature or coating them according to different needs. Doxorubicin is effective and widely used cytostatic agent, but when administered as a free drug it has often severe side-effects, like cardiotoxicity. Goal of this thesis is to determine appropriate manufacturing parameters and verify adequate shelf-life of ICG-Doxorubicin liposomes, that they are applicable for future in vitro experiments. Then survival of HepG2 cell line under flow in Quasi-Vivo®-equipment is determined, after which A549 and HepG2 will be then combined into one two-cell model. Finally, a simple illumination experiment in this cell model with previously made liposomes is conducted, and the effect in whole system is examined. Using protocol presented in this thesis it is possible to produce successfully and repeatedly liposomes with both ICG and doxorubicin encapsulation over 70%. Their shelf-life was at least 14 days when stored in 4°C protected from light. This was determined to be sufficient for in vitro testing. Cultivating A549 and HepG2 cell lines combined in the same system with shared media and fluid flow conditions was successful. Neither of the cell lines show significant difference in viability when compared to static control. When light-activating liposomes are administered to the system and then illuminated, from preliminary results we can see significant difference in drug effect. Both illuminated chambers and off-target chambers connected via Quasi-Vivo® show increased suppression, which shows promise that this in vitro model would be useful for future experiments.
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(2022)The problems caused by hypromellose in sterile filtration of ophthalmic products in the pharmaceutical industry were investigated. The research project was performed at NextPharma Oy's ophthalmics manufacturing facility in Tampere during the autumn of 2020. Hypromellose is an excipient commonly used in ophthalmic products as a viscosity enhancer to prolong the contact time of the preparation on the eye surface. In the ophthalmics compounding process, hypromellose is first dispersed by slowly sprinkling it into a hot solution and thoroughly mixing, after which the solution is cooled to room temperature. During cooling, the hypromellose dissolves and gels, increasing the viscosity of the solution. Incomplete dispersion or dissolution of hypromellose during the manufacturing process can slow down the filtration rate or even clog the filter completely due to undissolved hypromellose polymer material. Hypromellose is an industrially produced cellulose derivative that often contains some amounts of unreacted cellulose and other sparingly soluble polymer particles as impurities, which can also cause problems in filtration processes. Sterile filtration is a commonly used sterilization method for ophthalmic products, in which the prepared bulk solution is filtered through a 0.1 to 0.2 µm pore size filter membrane into a sterile receiving vessel. Due to the very small pore size, sterile filters are easily clogged if the solution contains poorly dissolved material. The purpose of this work was to collect additional information on the possible causes of clogging caused by hypromellose and to determine whether the filterability of a solution containing hypromellose can be improved by optimizing the manufacturing process parameters. The design of experiments was prepared, creating a two-level full-factorial test matrix without replicates and with three centre points. Four different process parameters were used (mixing time, mixing speed, dispersion temperature, and cooling temperature). Minimum and maximum levels for the parameters were obtained in the initial tests, after which the test solutions were prepared and filtered in a randomized order according to the test matrix. The aim of the screening was to find out which parameters were affecting the filterability and what would be their optimal combination that would maximize the filtration rate and the yield of filtration. Finally, the optimized parameters were used to test different batches of hypromellose, comparing the results to previous filtration tests. Additionally, an alternative hypromellose dispersion method was tested to minimize the amount of insoluble material remained during the dispersion and cooling steps. Of the parameters tested, mixing speed was the least significant, while cooling temperature had the most effect on the filtration results. The solutions with lower cooling temperature had better filtration results, which may be due to reduced aggregation of hypromellose due to increased hydration of the polymer chains. The temperature behaviour of hypromellose solutions could be an interesting subject for further investigation. Longer mixing times and higher dispersion temperatures produced slightly better filtration results on average, but the differences were not statistically significant. Most challenging in the study was controlling the temperature and mixing of the solutions, and the retention of insoluble hypromellose material at the walls of the compounding vessel. The alternative dispersion method gave promising preliminary results, but the method still requires further testing. It would be important to also find the root cause of the filter clogging mechanism e.g., by further analysing the clogged filter membrane. The study provided additional useful information of the behaviour of hypromellose solutions in solution preparations and during sterile filtration, which has been helpful in solving production problems.
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(2024)Vascular endothelial growth factor C (VEGF-C) is a key lymphangiogenic protein and potential therapeutic target, but its production in bioactive form from bacteria has been challenging. This study focused on the purification method of VEGF-C from Escherichia coli (E. coli) using three-step chromatographic approaches involving anion exchange, hydrophobic interaction, and size exclusion chromatography. While the major purified species migrated at the 35 kDa size, it lacked biological activity in a Ba/F-3-VEGFR-3 bioassay, likely due to interference from the partially cleaved maltose binding protein fusion tag. The maximum yield of 0.311 mg of VEGF-C per liter of bacterial culture represented a modest 3.11-fold increase over previous Ni-affinity chromatography but a 1.93-fold decrease compared to amylose affinity chromatography purification. Further work is needed to optimize tag removal and purification to enable larger-scale production of bioactive VEGF-C for research and potential therapeutic applications. While this study demonstrates conventional chromatography can purify VEGF-C, but highlights challenges in obtaining high yields of the bioactive VEGF-C.
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(2016)Prolyl oligopeptidase (PREP) is a serine protease which is extensively present in the mammalian system and especially abundant in the brain. Despite the long research history of PREP its physiological function has remained unclear. PREP has been suggested to regulate the functions of many bioactive peptides by hydrolysis and on the other hand to participate in several intracellular processes probably via direct protein-protein interactions. One of the functions suggested for PREP is the regulation of the brain neurotransmitter systems and based on, for instance, the location in the brain PREP has been connected to both excitatory and inhibitory neurotransmitter systems. The literature review of this thesis first describe the brain neurotransmitter systems associated to PREP in general with some examples of diseases related to their malfunctions. In addition the structure of PREP and its location in the brain, both subcellular and cellular levels, and in distinct neurotransmitter systems, are presented, after which the different proposed functions for PREP are reviewed. The aim of the experimental part of this thesis was to investigate the effects of PREP on the brain neurotransmitter concentrations in the mouse nigrostriatal pathway and also to mouse motor behavior. The main research methods were microdialysis, tissue assays and cylinder test. The study was composed of two sections with five week duration each. The first section was performed with wild-type mice expressing naturally PREP and the second section with PREP-knockout (ko) mice and their wild-type littermates. The mice were injected unilaterally above the substantia nigra with adeno associated (AAV1) hPREP viral vector or with AAV1-eGFP (green fluorescent protein) viral vector as a control treatment. The cylinder test was carried out before the injection, and two and four weeks afterwards. Microdialysis was used to study the actions of PREP on the extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), gamma-aminobutyric acid (GABA) and 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT). In addition to the baseline assay the concentrations were measured after two amphetamine treatments (10 and 30 µM) administered via the microdialysis probe. The probe guide cannulas were inserted to mice striatums 1-2 weeks before the microdialysis measurement. In the end of the experiment the tissue concentrations of DA, DOPAC, HVA, 5-HT and 5-HIAA were measured from striatum and substantia nigra. Both the microdialysis and tissue sample concentrations were quantified with high performance liquid chromatography. In the first study section the PREP enzyme activity was also determined from striatum. Neither the complete deprivation nor over-expression of PREP in the nigrostriatal pathway had clear or consistent effects on the levels of neurotransmitters studied when compared to naturally occurring PREP expression. When comparing the differences between control treated groups of PREP-ko and littermate mice, a greater amphetamine stimulated DA-levels was seen in the former group proposing negative regulatory influence of PREP. In both study sections the tissue assay results were difficult to interpret due to observed responses also with AAV1-eGFP control treatment in comparison with untreated side of the brain. This was seen as a lower DA- and DOPAC-levels in substantia nigra and thus the meaning of the changes caused by PREP treatment is hard to comprehend. The results of the cylinder test may implicate some protective effect of the PREP-ko-genotype against viral vector injections in general. Then again the existence of compensatory mechanisms is possible when using knockout animals and thus the genotype differences are hardly ever unequivocal. The results of this thesis do not suggest outright regulatory effects of PREP on the neurotransmitter functions in the mouse nigrostriatal pathway although the confirmation of this requires further studies, especially in regard to GABAergic and glutamatergic systems. Studies should include a scale of different behavioral tests of motor activity and repeated microdialysis experiment with some defining method changes. The possible function and mechanisms of PREP as a regulator of neurotransmitter intake or release is rationale to study at molecular level with applicable methods.
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(2010)Prolyl oligopeptidase (POP, E.C. 3.4.21.26) cleaves short peptides, of less than 30 amino acid long, at the C-side of an internal proline. It has been associated with many pathophysiological processes, such as neurodegeneration and inflammation. At the moment there are no studies that have been focused on POP function in multiple sclerosis (MS). A preliminary study in a Spanish cohort reported altered POP activity in plasma samples of patients with relapsing-remitting multiple sclerosis (RR-MS) compared with healthy controls. Also they observed increased levels of the endogenous POP inhibitor in plasma samples of patients with RR-MS. The first objective of this study was to evaluate the POP activity levels in serum and cerebrospinal fluid (CSF) samples from RR-MS patients and healthy controls in a Finnish population using a kinetic fluorescence assay. The seral levels of the endogenous POP inhibitor were also investigated by preincubating recombinant porcine POP (rPOP) with serum and determining the percentual decrease of POP activity compared to basal rPOP values (inhibitory capacity %). The second objective of this study was to purify and characterize the endogenous POP inhibitor in serum. In order to accomplish this goal, different biochemical and biophysical features, such as temperature resistance and filtering cut-off were tested. Also a combination of chromatographic approaches (affinity/anion exchange/hydrophobic interaction chromatography) with polyacrylamide gel electrophoresis and protein staining was used. All the differences observed in POP activity/inhibitor levels (serum, serum with DTT, CSF) between healthy controls and patients with RR-MS in this study did not reach statistical significance due to low values in all the samples. However, the trends in all the measured parameters were similar to the preliminary study in a Spanish cohort. Thus, the data supports further, more comprehensive, studies on the role of POP in MS. After series of chromatographic runs, a mass spectrometry analysis revealed the endogenous POP inhibitor to be α2-macroglobulin, a panprotease inhibitor in serum. α2-Macroglobulin has also been associated with MS, thus this finding substantiate the relationship between POP and MS.
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(2013)Spray drying is one way to dry protein medicines and it has many advantages compared to other drying methods, for example it is a fast process. In spray drying high temperature and mechanical stress can inactivate the protein. Disaccharides are generally used as protective agents of protein in spray drying because they have an ability to protect the structure of the protein during drying and storage. Aim of this research was to study the stability of the protein during spray drying and storage by using β-galactosidace as a model protein. Aim was also to characterize the physical properties of trehalose and melibiose and to study how well they protect the protein. Some of the central matters to be examined were the glass transition temperature, crystallinity, water activity, yield of the spray dried powder and protein activity. Especially studying the properties of melibiose in spray drying was important because it has not been used before. The study also included the optimization of the process parameters to be suitable for the product. Trehalose and melibiose transformed to an amorphous form during spray drying. Both XRPD and DSC showed an amorfous form. Trehalose and melibiose proved to be good protective agents for the protein during spray drying and storatge probably because they remained their amorphous structure. β-galactosidase remained activity very well. Optimizing of the process parameters was successful because protein remained its activity and still the powder was quite dry and yield was good. The changes in the structure of the protein were studied with FT-IR but the amount of the protein was too small. Problems caused by the spray drier may have an effect to the results, but on the other hand the spray dryer was made to work optimally.
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(2012)The burden of diabetes is increasing globally as the number of people with diabetes reaches over 220 million. Over 90 per cent of these people are suffering from type 2 diabetes. This condition is primarily defined by the chronic increase in blood glucose level or hyperglycemia. Type 2 diabetes is characterized by insulin resistance and is usually associated with abnormal insulin secretion. Insulin resistance is a state where normal amount of blood insulin is inadequate to increase glucose uptake in the most important target tissues of insulin. Numerous reports demonstrate that oversupply of lipids leads to loss of insulin activity and the formation of type 2 diabetes. Protein kinase C (PKC) isozymes comprise a family of serine/threoninekinases, which have a regulatory role in a multiple cellular processes. PKC!-isozyme activity is known to play a role in insulin resistance and therefore in type 2 diabetes. Free fatty acid (FFA) induced insulin gene function inhibition is associated with phosphoinositide dependent kinase1 (PDK1) independent phosphorylation of PKC!-isozyme in the most important insulin target tissues. Phosphorylated PKC!-isozyme causes insulinreceptor gene expression inhibition. Present study is part of a VHH-antibodies related research where the goal is to characterize these antibodies and to find out their effects on protein kinase C. VHH-antibodies are Ilama derived antibodies which contain a single heavy-chain variable domain, that is fully capable of antigen binding. In this work, we studied VHH-antibodies binding to PKC!-isozyme and its functional domains. PKC!-isozyme and its domains were produced in Sf9-insect cells. The binding was studied using Western blot and immunoprecipitation assays. In addition, the binding of 368 VHHantibodies to PKCε-isozyme's domain 2 were studied. With Western blot, it was discovered that E7-VHH-antibody binds to PKCε-isozyme full length and to domain 3. Other VHHantibodies tested in Western blot did not bind to PKCε-isozyme. Seven VHH-antibodies bound to PKCε-isozyme in immunoprecipitation. All of these VHH-antibodies bound to the full length and to domain 3, but not to other domains. In radioligand binding assays none of the VHH-antibodies bound to domain 2 that is the binding site to the endogenous PKCε-isozyme activator diacylglycerol (DAG). The results gathered with these three different methods were in line with each other. As the results gained from Western blot and immunoprecipitation show, all the VHH-antibodies, that bind to PKCε-isozyme, bind to its domain 3. With this study, we succeeded to gather new information about the binding of VHH-antibodies to PKCε-isozyme and its domains. The exact binding site has not been studied with so many VHH-antibodies before this study. Moreover, we also exploited methods that have not been used in this context before.
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(2015)Lead molecule search is the first part of drug design. This process can be done using computerized docking of ligands into target proteins. Usually this requires expensive software and powerful computer systems specifically made for the process. There are however some programs that are available for free and can be run on home computers. The purpose of this Master's Thesis was to see how these free software can be used for the task of docking and also to create a method or a guideline for such work. Protein kinase C (PKC), a popular target for drug design, was chosen as a target of inhibitor design. PKC is part of a larger family of serine/threonine kinases and formed of 10 isoforms all with different effects on cellular functions. The large amount of related kinases and the similarities in their sequences make finding selective inhibitors a difficult process. Homology models of all PKC isoforms in three known conformations solved by x-ray diffraction (pdb: 1XJD, 2I0E and 3A8W) were created using Modeller. Into these models a set of possible ligands from the free database of molecules ZINC was docked using Autodock Vina utilizing a script created for docking multiple ligands into multiple targets. The dockings resulted in some interesting results. Six molecules were recognized as possible lead molecules for further research. None of these molecules had any patents or previous results of protein kinase inhibition connected to them. The most interesting result was the finding that coluracetam, a nootropic drug of the racetam family, might be a protein kinase inhibitor. Racetams are usually considered drugs that lead to PKC activation. It has been proposed that inhibitors may prolong the lifetime of kinases in the cells leading to increased activity in the long term. In our opinion coluracetam might prove to be a good tool for studying the complex way kinase activity is modulated. The methods and scripts used in this work will be released for free use.
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(2014)Proteins are endogenous molecules that carry out most biological functions in vivo. They are called as the biological workhorses. Proteins are made up of polypeptide chains that usually fold in the three dimensional space to adopt a native stable conformation. Stability of proteins is dependent on the interplay of environmental factors (pH, temperature, ionic strength). For most proteins, the biological function closely relates to the structural attributes of the protein. Misfolding or unfolding of proteins often result in aggregation. Protein aggregation in vivo is known to cause debilitating and fatal diseases such as Alzheimer's, Huntington's, Parkinson's and age related macular degeneration (AMD). Instability (physical and chemical) of proteins in vitro is believed to result in aggregation. This is a huge concern for the biopharmaceutical industry as it not only limits the effectiveness of the manufacturing process but also poses a great risk of fatality in vivo due to the immunogenic nature of the aggregates. Mechanisms of protein aggregation are complex and not well understood. Regulatory requirements for patient safety in biopharmaceutical products require characterization and analysis of aggregates in protein drug formulations. This review provides an overview of protein aggregation in general and highlights the different analytical methods used to characterize protein aggregates in biopharmaceuticals. Neurotrophic factors influence survival, differentiation, proliferation and death of neuronal cells within the central nervous system. Human ciliary neurotrophic factor (hCNTF) has neuroprotective properties and is also known to influence energy balance. Consequently, hCNTF has potential therapeutic applications in neurodegenerative, obesity and diabetes related disorders. Clinical and biological applications of CNTF necessitate a recombinant expression system to produce large amounts of functional protein. Previous studies have reported that recombinant expression of CNTF in Escherichia coli (E. coli) was limited by low yields and the need to refold the protein from inclusion bodies. In this report, we describe a strategy to effectively screen fusion constructs and expression conditions for soluble hCNTF production in E. coli. Most conditions tested with the codon optimized hCNTF sequence in fusion with soluble tags resulted in soluble expression of the protein. The construct 6-His-CNTF showed soluble expression in all the conditions tested. Our results suggest that codon optimization of the hCNTF sequence is sufficient for soluble expression in E. coli. The recombinant hCNTF was found to bind to CNTFRα with an EC50 = 36 nM.
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(2016)In the United States pharmacists have prescribed medicines and managed patient's drug therapy since the 1970s, and in the United Kingdom pharmacists have been authorization to prescribe medications since 2003. The discussion about the right of Masters of Science in Pharmacy will be renewed prescriptions during the last decade in Finland but few Finnish studies have been published from the subject. In the document Medicines Policy 2020 published by Ministry of Social Affairs and Health states that by prescribing should be used cost-effective modes of operation. The knowledge about pharmacist prescribing benefits and costs, and also prescribing practice in Finland, is needed to evaluate the cost-effectiveness of pharmacists' authorization to prescribe and to support the decision-making concerning pharmacist prescribing. The aim of this master's thesis is to gather all existing knowledge about the economic and other effects of pharmacist prescribing using a systematic literature review method. The aim of theoretical part of this master's thesis is to explain the Finnish prescribing, the participation of pharmacists in drug therapy management in Finland and internationally pharmacist prescribing. The empirical part of this master's thesis is also to assess the quality of the studies of pharmacist prescribing benefits and costs using quality assessment checklists. In addition, this thesis describes the principles of the cost and benefit analyses, economic evaluations and systematic literature reviews. As a result of the literature search were found 1825 references. Based on the inclusion and exclusion criteria, 17 studies were selected to include in the systematic review. Of these studies three were economic assessments, 8 randomized controlled trials and 6 observational studies. The quality of these studies was assessed using four quality assessment checklists. On the basis of a systematic literature review pharmacist prescribing has been studied in the treatment of type 2 diabetes, hypertension, dyslipidemia, anticoagulation, chronic pain, emergency contraception and minor ailments and renewal of long-term medicines. Pharmacists reduced blood pressure by providing follow-up care with prescribing compared with the usual care, but not compared with the case management, which does not include prescribing. In addition, the follow-up care was to improve the treatment results of type II diabetes. The results obtained in the care of dyslipidemia were partly unclear. In the clinic follow-up care with prescribing could be reduced LDL-cholesterol, but not the risk of cardiovascular disease compared with the control group. In the pharmacy follow-up care had no effect on the treatment of patients with LDL-cholesterol compared with the control group. In addition, pharmacist prescribing improved how well patients stayed within INR target range. Pharmacist medication review with pharmacist prescribing achieved in the care of chronic pain patients differed few from the results of pharmacist medication review with feedback for a general practitioner. Pharmacist prescribing could reduce errors in inpatient medication compared with usual care. Much uncertainty is connected to the results of the study. The limited amount of studies, heterogeneity of the studies and methodological quality make the evaluation of real effects more difficult. The included studies of pharmacist prescribing were so heterogeneous. In addition treated disease, assessed benefits and scope of working environment were varied in included studies. Pharmacist prescribing was often studied as part of other care or pharmaceutical service, such as chronic disease management or medication review. The quality assessment of the included studies revealed several sources of bias. The available research information is the insufficient reliable evaluation of economic and other effects of pharmacist prescribing and the need for the further research is big.
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(2020)Background. Critical thinking skills, which are an aspect of generic skills, are related to the success students have in their university studies and working life after graduation. When it is considered whether the current degree programs and education systems support sufficiently the development of the skillset needed in the future working life of a university student, one can focus on examining the development of critical thinking skills of a student. Due to the lack of scientific studies on critical thinking, research should be done on the field of pharmacy to gather information on the critical thinking skills of master of pharmacy students and to determine, if the master’s degree program in pharmacy is generating the kind of professionals needed in the working life. Aim. The main goal is to study the level of critical thinking skills possessed by students in the beginning of their Master of Pharmacy studies. Combining the theoretical background and empirical study is considered in choosing a suitable method for the study. The method chosen for the study has to be applicable to determining a student’s ability to interpret, analyse and evaluate information, based on which a student consciously arrives on a conclusion while taking into consideration the context and different point of views of students. In addition to studying critical thinking skills, the aim is to analyse the students’ quality of argumentation and the use of references in comprising quality arguments. Methods. The studied set of students comprised of 17 students on their first year in the Master of Pharmacy program in University of Helsinki. The study was performed using a constructed-response task which was based on a real-life problem and was composed of three statements the students had to address utilizing the provided materials. When answering an open question, a student has to be able to analyse, evaluate and synthesize information from different sources. Based on this process, the student must demonstrate in their own words the relevance of the processed information and to construct a coherent essay that also utilizes the provided sources appropriately. The critical thinking skills of the students were evaluated from three aspects: the relevance of the content, processing of information and augmentation. A table for evaluation and classification of the data was created based on the literature study on critical thinking. According to the table, the studied material was divided into three categories. Category 1 entailed students with essays showing the lowest level of critical thinking skills while category 3 entailed students with essays showing the highest level of critical thinking skills. Results and conclusions. A deficiency in the level of critical thinking and argumentation skills possessed by the students was found, which has been encountered in previous studies, as well. All in all, only three out of the studied 17 students, showed impressive critical thinking skills. Most of the student (82%) showed defective argumentation, and more than half (65%) had problems with referencing. In addition, all but one student struggled in utilizing the information gathered from the reference materials. Based on the results, it is important to focus on developing the critical thinking skills of the students in the master’s program in pharmacy. To further study the matter, the same study should be performed on students at the end of their master’s studies to determine if the teaching and evaluation methods in the master’s program in pharmacy are sufficient in developing adequate critical thinking skills
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(2015)There are dozens of bromotyrosine alkaloids extracted from the marine sponge Pseudoceratina purpurea. Bromotyrosines have for example antibacterial, antiviral and antitumor activity in vitro and therefore bromotyrosines are potential drug lead molecules. By far, bromotyrosines have been extracted from different marine sponges of the Verongida order for the use in biological activity research. Collecting marine sponges by scuba diving is neither fast nor ecological and therefore finding an effective synthesis strategy is vital so that the research could continue. One new bromotyrosine, purpurealidin I, was found from the marine sponge Pseudoceratina purpurea in the four year (2010-2014) Marex-project. The aim of this thesis was to synthesize the compound purpurealidin I and its derivatives. Synthesized compounds were tested against hepatitis C and chikungunya viruses. It is important to find new potent drug molecules, because approximately 350 000-500 000 people die from hepatitis C and there is no curative medication for the chikungunya. Purpurealidin I is synthesized from tyrosine and tyramine parts, which will be put together to form an amide bond in the final step of the synthesis. The synthesis of purpurealidin I was not completed during the Master's thesis. However there were two purpurealidin I derivatives and four purpurealidin I tyramine part derivatives that were successfully synthesized. One of the compounds is purpurealidin E, which can be extracted from the sponge Pseudoceratina purpurea. The t-Boc derivative of purpurealidin E was examined against hepatitis C and chikungunya and the compound showed moderate activity against hepatitis C virus, but it wasn't active against chikungunya virus. The original plan to synthesize purpurealidin I is possible, although some reactions and purification of crude products need to be optimized in order to get better yields. For the future research derivatives of the t-Boc derivative of purpurealidin E should be synthesized and studied against hepatitis C virus.
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(2023)Changes in environmental and psychological factors have greatly influenced human eating behavior, leading to increasing rates of overeating. In the long-term continuous overeating causes the body to accumulate an excess amount of body fat tissue, which is a leading factor in the development of obesity and obesity related diseases that reduce the quality of life. Despite the available treatment options, the prevalence of obesity has been increasing worldwide. In avoiding obesity and obesity-related diseases, it is crucial to understand the outside factors which lead to obesity and the mechanisms which regulate body energy balance. The brain's serotonin system seems to play a significant role in regulating both energy balance and the tendency that promotes an overeating type of eating behavior. The properties of psychedelics to affect human's emotional state and thus modulate behavioral patterns through the brain's serotonin system has aroused interest in psychedelics for their possibilities in treating eating behaviors that promote overeating which results in obesity. This study aimed to examine the dose-dependent effect of three different psychedelics on eating behavior in mice and evaluate their potential drug therapy properties in overeating indulged obesity. In total, 16 female mice were trained to perform in an operant setting used in behavioral experiments measuring appetite and motivation for food reinforcers. The psychedelic-derived changes were observed in mice's eating behaviors by reward deliveries received during the trials. The examined psychedelics (lysergic acid diethylamide (LSD), psilocybin (PSI), and 25CN-NBOH) showed no statistically significant changes in the mice's eating behavior in terms of appetite and motivation. However, while statistically non-significant, some changes in hunger and motivation were observed in the mice, for example, in days followed by the dosage of the psychedelics. These results indicate no effect on appetite and food motivation by the studied psychedelics.
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(2012)Pyrazoles are five-membered nitrogen containing heterocycles, whose derivatives can be widely used in medicinal chemistry. One of the most common ways to produce pyrazoles is 1,3-dipolar cycloaddition, where the dipole containing heteroatom is reacting with a dipolarophile, and forming a cycloadduct. Among others, mesoionic sydnones have been used as dipoles in 1,3-dipolar cycloadditions of pyrazoles. During the last decades solid phase methods, where either a dipole or dipolariphile is being temporarily bound to solid support, have been exploited in 1,3-dipolar synthesis. With the aid of solid phase methods, the synthesis can be controlled chemically by protecting groups that react easily. Also the isolation and purification can be made easier by using these techniques. The 1,3-dipolar solid phase methods can be combined with microwave techniques, to make the synthesis shorter and more effective. The goal of this work was to synthesize new N-unsubstituted pyrazoles, starting from sydnones bound to solid support and alkynes, with use of 1,3-dipolar cycloaddition reaction and to purify and analyze prepared compounds. The aim was also to develop a new 1,3-dipolar solid phase method so, that the end products could be cleaved easily in a traceless manner, and that there would be minor need for purification. There was also an aim to make the last step of the synthesis faster and easier with microwave reactor, and by using this method to standardize the conditions used in the cycloaddition-dehydration reaction step. The AMEBA-resin was chosen to be the solid support in this synthesis. Its traceless cleavage by trifluoroaceitic acid made possible not only the formation of the desired structure, but also effortless purification of the end product. The amino group of pyrazole was protected by the solid support during the N-nitrosation, so that after the traceless cleavage of the resin, N-unsubstituted pyrazoles were obtained. By changing the amino acids used in this synthesis, it was possible to alter the structure of the synthesized pyrazoles, and to create four structurally new pyrazoles. Microwave method used during the last step of synthesis for heating shortened the reaction step significantly, and also the yields of end products were better compared to conventional heating. During this work a functioning and developable 1,3-dipolar solid phase method was created, that can be utilized to synthesize pyrazoles and other compound of similar nature also the in future.
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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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