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  • Aaltonen, Kalle (2010)
    Rheumatoid arthritis is an inflammatory autoimmune disease with prevalence of 0,8 per cent of Finnish people. Rheumatoid arthritis may lead to immobility and premature death. Treatment of Rheumatoid Arthritis includes disease modifying anti-rheumatic drugs and surgery. TNF-blockers are efficacious new drugs, which halt the progression of joint destruction caused by inflammation. The first TNF-blocker to receive permission of the national agency for medicines was Infliximab in 1999. Since then Infliximab has been followed by Etanercept, Adalimumab, Golimumab and Certolizumab. TNF-blockers have been found to be more efficacious than placebo in both clinical trials and register studies. In addition they are considered to be safe enough for clinical use despite the increased risk for tuberculosis and certain cancers. The number of patients annually treated with TNF-blockers in Finland increased threefold between 2004 and 2008. In 2008 the medication costs per patient were 11 669€ for Etanercept and 13 074€ for adalimumab. Systematic literature review is a study, which searches, identifies and combines individual studies. Usually Systematic reviews include a meta-analysis, which uses statistical methods to combine the results of the studies. Meta-analysis aims for increasing power and generalisibility of the studies and reducing the potential bias in individual studies. In order not to introduce bias by itself the systematic review must be done following the methods approved by the scientific community. In addition the process must be documented in detail. Following a predefined search strategy the systematic literature search found 5308 references. After a process involving the evaluation of the patients, intervention, control, outcomes, study design and the risk of bias 27 studies were selected to be included in the systematic review and meta-analysis. Of the included studies, nine had adalimumab, six had etanercept, five had infliximab, four had golimumab and three certolizumab as intervention. TNF-blocker was used either alone or in combination with methotrexate whereas control was either placebo or methotrexate. Altogether, there were 11 533 patients in the intervention group and 9027 in the control group. The results of the meta-analysis indicate reveal that the patients treated with TNF-blockers are twice as likely to reach a 20 % increase on ACR criteria compared to control patients. The likelihood to reach improvements of 50 and 70 % was 3 and 3.5 times higher, respectively. There were no statistically significant differences in efficacy between individual TNFblockers. Increasing the dosage of a TNF-blocker did not increase efficacy. However, combination of TNF-blocker and methotrexate was superior to monotreatment of TNF-blocker without increasing the likelihood of discontinuation of treatment. There were no statistically significant differences between the efficacy of TNF-blocker monotherapy and methotrexate. Adalimumab, infliximab and certolizumab lead more often to treatment discontinuation compared to etanercept and golimumab, which do not differ from control. This systematic review probably found all studies that investigated the efficacy of TNF-blockers in a randomized controlled trial. Study selection and evaluation were based on widely accepted methods. This study has two weaknesses. Firstly, literature search and study selection and evaluation were done only by a single researcher. Secondly, unpublished studies and study results were not actively obtained outside electronic databases.
  • Pakarinen, Tiina (2014)
    Clinical pharmacy is defined as a service which a pharmacist provides for example to a ward or a medical center. In Finland clinical pharmacy (or ward pharmacy) was started in the 1980s but it hasn't expanded widely until at the end of the 2010s. Need for cost-effectiveness research has been under discussion because of increasing health care costs. This kind of research helps to choose the most effective services. Naturally also clinical pharmacy is under effectiveness consideration. A systematic review was conducted considering the cost-effectiveness research of clinical pharmacy. The aim of this review was to find clinical pharmacy interventions which have been proven costeffective. Literature research found 7 articles. Three of these studied pharmacokinetic patient surveillance and in the rest four articles pharmacist worked as a part of multidisciplinary team. In six studies the cost savings were greater than the costs. The other part of this study was about clinical pharmacy in the hospital district of Helsinki and Uusimaa (HUS). Data was collected from Helsinki University Central Hospital (HUCH) wards which had had clinical pharmacy services during the years 2009-2012. Collected data included clinical pharmacy costs and amount of work gained with those costs, drug consumption, drug waste amounts, amounts of drugs returned to HUS-pharmacy and amounts of HaiPro-reports. Collected data was presented as a time series. The costs of clinical pharmacy had followed the trend of other health care costs during 2009-2012. Wards with clinical pharmacy had somewhat larger amount of drug waste than the other wards. Amounts of drugs returned to the pharmacy were greater in the wards with clinical pharmacy. The amount of HaiPro-reports grew by a factor of 15 from 2009 to 2012. Especially amounts of drug administration errors and errors in writing down prescriptions were greater in clinical pharmacy wards. The data in this thesis describes only a small part of clinical pharmacists' work in the HUCH area. Making final conclusions about the cost-effectiveness of clinical pharmacy isn't possible with this data. The systematic review can give ideas to improve clinical pharmacy in HUS in a more cost-effective direction.
  • Kokkonen, Niina (2011)
    Segregation or demixing of particle systems is a phenomenon where one component of a homogeneous powder mixture tends to separate from the other components. The segregation tendency of powder depends on the characteristics of particles, environmental conditions and interactions between particles. A huge number of segregation mechanisms are presented in literature and even small differences between the properties of particles and particle interactions can lead to a completely different segregation mechanism. The segregation phenomenon is very essential from the perspective of pharmaceutical industry. However, the phenomenon is not yet sufficiently well known in order for segregation to be systematically avoided. Current research on segregation is largely based on learning through trial and error. Therefore, innovative research methods are needed to understand the true segregation phenomenon. The purpose of the experimental part was to develop and basic test the method of testing the segregation behavior of different particle systems and use this method to examine the segregation behavior of pharmaceutical mixtures of granules and pellets. The aim was to prove that the operating principle of the developed Babel-device is suitable for examining the segregation behavior of particle systems, but the trials carried out mainly consisted of method and device testing. The problems were composed of the limitations imposed by the Babel-device, particle electrification and particle interactions. Linear approaches used were insufficient for creating segregation by the Babel-device. Convection resulting from vertical shaking prevented the generation of segregation. In conclusion, we can say that the Babel-device measures well and reproducibly, and it is able to distinguish different particle sizes and different particle size distributions from each other. The development aim of the device would be to obtain a more visible segregation in the powder mixture as a result of shaking. Thus, we would be able to draw conclusions from the segregation behavior of the powder mixture and the prevailing segregation mechanisms in the system. Further development of the device and the method could provide useful additional information which would contribute to better understanding of the phenomenon of segregation.
  • Nikkilä, Tiiu (2019)
    Background: Continuous manufacturing has been utilized for decades in many industries since it has many advantages compared to batch manufacturing. Therefore the interest towards continuous processes has arisen also in the pharmaceutical industry. Also, the strict regulations characteristic of pharma industry have started to change more favorable towards continuous manufacturing when the possibilities of continuous processes to produce higher quality products faster and more efficiently, have been proven in many researches. Objectives: Objectives of this thesis were to clarify the effect of the material characteristics on material flowability from continuous feeders and to study how different toolings, like feeding screws, affect the feeding of materials with different characteristics. Based on these results, a possibility to model the feeding results of a material based on only some measured material characteristics was also under investigation. The aim was to develop a clear and systematic procedure which would simplify the determination of the most suitable equipment when starting to feed a new material. Methods: The similarity of flowability of various pharmaceutical powders from continuous feeders was studied. First material characteristics affecting material flowability from a feeder based on literature was determined from 26 pharmaceutical powders. Following this, six materials were chosen to be studied with gravimetric powder feeders using different kinds of research frames. The six materials formed three material pairs, in which two materials had clear similarities in the flowability characteristics. The reason for this was that the flowability from feeders with similar materials could be compared. The feeding of materials was determined investigating the feed rate capacity and accuracy of feed rate of material. Also, the effect of feeder screws and the speed of the screws on the feeding capability of a material was investigated. A model to predict the feeding result based on material characteristics was built using PLSand MLR-methods. Results: The prediction of material feeding was not possible with PLS- and MLR-modeling methods. The feeding of similar materials was wound to be alike. Poor flow characteristics correlated with poor feeding results. PCA- and cluster analysis were found suitable to define the similarity of materials. Conclusions: The success of feeding of pharmaceutical powders is clearly affected by the material flowability properties. The feeding screws and screw speed affect the feeding accuracy, too. The prediction of feeding results of specific material, would need much more data to produce valid and trustworthy models. However, it seems highly possible to be able to build a model with more materials.
  • Salmelainen, Laura (2010)
    Neuronal nicotinic acetylcholine receptors are ligand-gated ion channel receptors that consist of five transmembral receptor subunits. They can form a functional receptor subtype solely out of alfa-subunits or out of a combination of alfa- and beta-subunits. The number of potential assembly of nicotinic receptor subunits is high because at least nine alfa-subunits (α2-α10) and three beta-subunits (β2-β4) have been recognized. The composition, location and pharmacological properties of different subtypes have not yet been fully characterized. However, it has been shown that the neuronal nicotinic receptors are involved in a wide range of physiological and pathofysiological processes especially in the central nervous system. Toxins from snakes and Conus -sea snails have proved to be important tools in neuropharmacological research, from which considerable information on structure and subunit combinations of the nicotinic receptors have been received. Receptors binding assays or autoradiographic experiments exploiting toxins have also been useful methods to locate the neuronal nicotinic receptors in mammalian brain. The aim of the experimental part of the Pro gradu was to characterize in vitro binding affinities of α-contoxin MII, α-conotoxin Vc1.1, neurotoxin II, α-cobratoxin and weak-toxin synthetized in Moscow and of well-known receptor ligands cytisine and methyllycaconitine to neuronal nicotinic receptors in SH-SY5Y- and SH-EP1-hα7-cell membrane preparations. SH-SY5Y-cells are known to express various neuronal receptor subtypes (α3* or α7) endogenously. For the SH-EP1-hα7-cells part, the cell line has been transfected with α7 nAChR-genes and it expresses only α7 receptor subtypes. Receptor competition studies were performed with [3H]-epibatidine (400 pM SH-SY5Y, 2000 pM SH-EP1-hα7) and the radioactivity was measured with a Microbeta- scintillation counter. [3H]-epibatidine was perceived to be displaced almost completely by cytisine and methyllycaconitine in both cell lines. In addition to this, the toxins were shown to bind to two distinct receptor-binding sites in SH-SY5Y-cells. Also α-contoxin MII and α-conotoxin Vc1.1 inhibited [3H]-epibatidine binding by biphasic manner, but the maximal displacement failed to be complete. From α-conotoxins only MII had affinity to α7 receptors in SH-EP1-hα7-cells. Neurotoxin II, α-cobratoxin and weak-toxin were not found to compete with [3H]-epibatidine for the same binding sites in SH-SY5Y-cells. The results confirm the assumption that cytisine and methyllycaconitine label various nAChR-subtypes. Instead, based on SH-SY5Y-cell assays α-conotoxins used in this study would seem to label spesifically only particular nAChR-subtypes. The receptor competition studies also confirm the prevalent conception that neurotoxin II, α-cobratoxin and weak-toxin do not bind to neuronal nicotinic receptor subtypes containing α3-subunits.
  • Saarinen, Tuomas (2015)
    The roller compaction is a dry granulation method which is commonly used in the pharmaceutical industry. The purpose of the roller compaction is to increase the particle size, narrow the particle size distribution and improve the powder flowability. In the roller compaction process, powder is fed between two press rolls. The relevant process parameters of the roller compaction (roll pressure, roll speed and feed screw speed) affect the formed briquette or ribbon density. The briquette is broken down and sieved by using a crusher. General problems of the roller compaction are incompressible fine powder and the low yield. AGS (Aerodynamic Granulating System) is a patented supplement for the roller compaction. Its operation is based on the air flow which sucks the fine particles out of the granule mix. The granules and the fine particles are collected into their own containers. When the system is fully optimized the fine particles can be recycled between the press rolls (a closed loop). In this case, it is possible to get close to 100 % batch yields. The experimental design of this study was a modified central composite design with three variables and two value levels which was used to find the optimal combinations of the process parameters. The purpose of this study was to compare the gas assisted and the conventional roller compaction methods. The physical properties of granules and tablets made of these granules were compared. The strengths and weaknesses in AGS process were also studied and development ideas for the future were planned. Microcrystalline cellulose was used in this study as a model excipient. The study showed that the granules made by the AGS require higher compression forces in tableting process than conventional granules. The reason for this could be the lower number of contact points between the particles, since the fine particles were removed from the granule mix. The low compression pressure, fairly fast roll speed and small sieve size created good quality granules. The flowability and compression properties of these granules were good as well as particle size distribution. In this study, any major differences were not observed between these two granulation methods.
  • Vieraankivi, Marika (2021)
    The ABCG2-protein is an ATP-dependent half transporter. It is found on apical membranes in intestine, liver, kidney, blood-brain barrier and placenta where it regulates absorption, distribution and elimination of many drugs, but also natural compounds and endogenous metabolites. Natural variation found on the ABCG2-gene can alter protein expression and transport activity. The altered function has been linked to pharmacokinetic changes and developing of diseases like gout. Studying natural ABCG2-variants and their effect gathers knowledge not only on their effect on pharmacokinetics but also on the ABCG2- transporters’ mechanism of function. The aim of this study was to combine an activating (I456V or H457R) and an inactivating (Q141K, F431L or T542A) non-synonymous single nucleotide variant in the same gene to study their combined effect on the ABCG2-transporter expression and active transport. Mutations were incorporated into the ABCG2- gene by site directed mutagenesis and the protein was expressed on HEK293-cells. The transport activity for Lucifer-Yellow and estrone sulfate was measured using HEK293-ABCG2-vesicles produced from cell membranes. The protein expression was measured with Western blot and mass spectrometry proteomics. Based on this study, different mutations together can alter each other’s effects, but the combined result is not always equal to the sum of variations. T542A-mutation did not show significant increase on the protein expression on any of the T542A-combinations, even though it has had such an effect in earlier studies. I456V, earlier expressed like wild type ABCG2, seemed to increase protein expression in all combinations. Q141K, F431L and T542A -mutations had lowering not expression dependent effect on the transport activity. F431L-mutation being so dominant that either of the two activating mutations could not restore the active transport in combinations. As seen before, H457R-variant seemed to cause a significant substrate specific activating effect on transport activity also in this study when combined with other mutations. However, H457R had a strong lowering effect on the protein expression and two of the combinations did not produce enough protein for active transport. As seen in this study, the ABCG2-doublemutations can cause altered ABCG2-function and lead to pharmacokinetic changes. These types of in vitro studies are important in studying these less common genetic variants which in lack of study subjects can be hard to study on clinical trials.
  • Mikkola, Vilhelmiina (2015)
    Organogels refer to gels whose liquid phase is composed of an organic solvent instead of water. Compared to hydrogels it is estimated that oil based organogels, alias oleogels, are able to improve the solubility and bioavailability of the poorly water-soluble drugs and also to promote the stability of the easily water-degradable drugs. Furthermore, it has been estimated that compared to fluid oil based products organogels are able, especially in veterinary medicine, to facilitate the administration of the drugs and other nutritive substances by guaranteeing more precise and more stable administration platform. The purpose of this work was to develop and to optimize the composition and the manufacturing process of the organogel based nutritional product for pets. Fish oil and solid active pharmaceutical ingredients were used as active components of the nutritional product but in addition for operating as a source of fatty acids fish oil also functioned as a liquid phase of the organogel formulation. In this work the fish oils were thickened with colloidal silicon dioxide. In addition to the silica different surface active agents; krill oil, lecithin or tocopherol; were also added to some of the formulations in order to enhance the gelation property of the colloidal silicon dioxide. Systematic design of experiments was utilized in the planning of the organogel formulation test series. Two different silicon dioxide grades and seven different surface active agents were used in this work. The three-dimensional structure of the organogel samples were examined by Cryo-TEM. The rheological properties of the organogel formulations were determined by dynamic rotation rheometer one week and 3 months after the preparation of the organogel samples. On the basis of the observations that were done in this work, certain levels of krill oil and lecithin grades Phosal® 35 SB, Phosal® 53 MCT and Phosal® 75 SA were able to enhance the gelation property of the silica-fish oil mixtures compared to the formulations that contained only plain silica or silica-tocopherol mixtures. Especially krill oil was found to be able to enhance the thickening effect of the silica-fish oil mixtures even when small concentrations and low shear rates were used whereas either high silica contents or high shear rates were needed to thicken the pure fish oil-silica mixtures. Although krill oil and lecithin grades Phosal® 35 SB, Phosal® 53 MCT and Phosal® 75 SA were, in certain concentration levels, able to enhance the thickening effect of the silica-based fish oil mixtures the predemands of the paste-like consistency, solidity and 2 years stability time were not fulfilled as desired. On the basis of the observations that were done in the pre-tests, it is however possible that either by using different krill oil and fish oil combinations or by using higher shear methods it could be possible to form the desired, stiff, paste-like, stable organogels at least with the help of krill oil and colloidal silicon dioxide.
  • Korkeamäki, Laura (2013)
    The status of herbal products has changed over time and due to changes in medicines legislation in Finland. The study period starts from 1964, when marketing authorisation procedure became obligatory for medicinal products. In 1994 medicines regulation introduced the term "herbal remedy" and in 2005 the terms "herbal medicinal product" and "traditional herbal medicinal product". In recent years there has been an increasing interest in medicines information regarding children. For example in 2007 a new paediatric medicines regulation was given by the EU. In Finland a new medicines information strategy was published in 2012 by the Finnish Medicines Agency. The aim of this study was to find out how the medicines information of herbal products regarding children has changed over time and changes in legislation. The material of this study were the documents of herbal products under medicines regulation in Finland 1964 - 2012. The information was gathered from summary of product characteristics, package leaflets, labellings and their predecessors. In total there were 195 products of which 189 had relevant documents for this study. The method of this study was content analysis. The information was collected from the documents to data sheets. The analysis was based on the legislative periods. Medicines information has become more accurate during the study period 1964 - 2012. Information was less accurate between years 1988 and 1995. The amount of medicines information has increased after the term "herbal remedy" and terms "herbal medicinal product" and "traditional herbal medicinal product" were introduced. Some of the changes in medicines information could be tracked to specific regulatory changes. The study gives historical perspective on the changes in medicines information of herbal products in Finland. It is clear that the legislative changes have limited effect on medicines information, if the amount of paediatric scientific studies is not increased. In the future there is a need to study the prevalence of the use of herbal medicinal products and traditional herbal medicinal products in children and in other population groups. There is also a need to study how the medicine information differs in herbal medicinal products and traditional herbal medicinal products and what are the differences compared to the information on dietary supplements.
  • Hirvisaari, Laura (2012)
    Estradiol is a female sex hormone which is metabolized to two different catechol estradiols. 2-hydroxyestradiol (2-OHE2) is normally the major catechol estradiol metabolite but breast cancer patients have increased amounts of genotoxic 4-hydroxyestradiol (4-OHE2) and it arises to predominant metabolite with these patients. These catechol estradiols can form reactive quinones that can bind to DNA and lead to mutations and finally cause cancer. Catechol-O-methyl transferase can add methyl groups and UDP-glucuronosyl transferase (UGT) glucuronic acid groups to catechol estradiols. These phase II enzymes play important role in the inactivation of catechol estradiols because only non-conjugated catechol estradiols can be oxidized to quinones. The aim of this study was to find out which human UGTs catalyze glucuronidation of 2-OHE2 or 4-OHE2, how many different glucuronides are formed and in which part of the substrate glucuronic acid is added. To answer these questions chromatography methods for 2-OHE2 and 4-OHE2 glucuronides were developed using HPLC. Eleven UGT-enzymes glucuronidate 2-OHE2. UGTs 1A1, 1A7 and 1A10 form two different glucuronides and UGTs 1A3, 1A8, 1A9, 2A1, 2A2, 2A3, 2B7 and 2B15 form only the second glucuronide. It was possible to detect three different glucuronides for 4-OHE2 but the amount of the first glucuronide was under quantification limit. UGT1A10 catalyzed the formation of the second glucuronide and UGTs 1A7, 1A8, 1A9, 2B7 and 2B15 catalyzed the formation of the last glucuronide. One aim of the study was to find out which part of the substrate is glucuronidated but this aim was not achieved because suitable standards were not available.
  • Niittynen, Ilona (2018)
    Medication-related events are a significant cause of in-hospital adverse events. Intravenous medication errors occur more frequently and are more likely to result in serious harm than other medication therapies. Closed loop medication management which seamlessly integrates automated and intelligent systems barriers, is used for reducing medication errors. The aim of this systematic review was to identify what kind of scientific studies exist regarding closed loop medication in intravenous medication therapy and barriers related to it. This study is part of a larger systematic review. The literature search indentified 2292 scientific papers. Of these, only 57 were included in the larger review since most of the references were excluded based on titles, abstracts or full-texts. Of these, 21 studies regarding closed loop medication management in intravenous medication therapy were included in this thesis. The studies conserned intelligent infusion devices, computerized physician order entries, clinical decision support systems, automated workflow management systems reducing compounding errors and bar-code confirmation of drugs and patients. According to this review, closed loop medication management potentially reduces medication errors related to intravenous medication therapy. It seems to be more effective to seamlessly integrate the closed loop medication management barriers to each other and to the medication management process than to implement the barriers separately. It’s important to plan the implementation carefully by a multidisciplinary team. In addition, the latest care guidelines need to be taken in to account. Significant resources must be allocated to training and engaging employees and to systematically maintaining and developing the process to manage the successful implementation of the process. This review provides valuable information for Finnish hospitals implementing the closed loop medication management since the concept is not yet well-known in Finland.
  • Kouvonen, Sonja (2024)
    To develop a closed-loop medication management process, monitoring the effects of medication should be integrated into patient information systems through structured recording methods. Sufficient documentation of medication monitoring is a prerequisite for implementing effective medication management and ensuring good quality, individualized care for patients. Medication management for patients with intellectual disabilities on the autism spectrum can be extremely challenging. The characteristics of intellectual disabilities and autism spectrum disorders, comorbidities, and polypharmacy make medication management and monitoring challenging. This study focused on patients with difficult behavioural symptoms. The study aimed to identify the most important symptoms to monitor in assessing the effects of medication in patients with intellectual disabilities on the autism spectrum. Additionally, it defined the time points from the initiation of medication when the effects should be assessed. The study was conducted as a two-round study using the Delphi consensus method in January-February 2024. The expert panel consisted of 12 experts in intellectual disabilities, autism spectrum disorders or in the field of medicine. Lists of behavioural symptoms, other symptoms, and monitoring time points were compiled for the study based on literature and the expertise of the research group. Experts were presented with a list of symptoms, and in the first round, symptoms that exceeded a consensus threshold of 50% proceeded to the second round. In the second round, experts ranked symptoms based on their importance for monitoring using Likert-scale questions. The data were analysed using quantitative and qualitative methods. Experts considered 9 behavioural symptoms and 22 other symptoms as highly important or important to monitor. The experts identified severe symptoms indicating self-harm or harm to others as the most critical behavioural symptoms to monitor. The most important other monitored symptoms included common comorbidities and symptoms within the patient group or adverse effects of medication. The effects of medication should be evaluated regularly, at least at the 4-week mark after initiating medication and after 3 months evaluations should be conducted at intervals of every 6 months. Monitoring the effects of medication was perceived to pose many challenges, and monitoring is not always carried out at a sufficient level. Many different symptoms should be monitored because patients are individual and present a variety of symptoms. It is essential to have a good understanding of the patient's condition before starting medication to assess the medication's impact on the patient's behaviour or other symptoms. The study highlighted the lack of structured monitoring forms and the need for monitoring tools.
  • Heinonen, Susanna (2010)
    Methods for the assessment of the bioequivalence (BE) of drug products are generally well-documented and the approaches for such studies are described in guidances issued by regulatory authorities throughout the world. While in general, the BE requirements of most regulatory bodies have much in common, in various instances specific issues and approaches may differ. In the literature part of the master's thesis these differences in the selected regulatory BE guidelines (Europe, United States and World Health Organization) was examined and also the scientific reasons behind these differences were considered. It was found that the prime differences were in the BE related issues in which the scientific community are not in agreement (multiple dosing, highly variable drugs, moieties to be measured (parent/metabolite), food effect studies etc.). The differences were also related to drug products that have biopharmaceutical, bioavailability (BA), pharmacokinetic, and pharmacodynamic properties that preclude the use of standard approaches that are outlined in regulatory guidelines. In the future the push for international harmonization of regulatory standards is hopefully leading to worldwide discussions and changes regarding BE and other components of the drug approval process (both new and generic drugs). Expensive in vivo BE studies are usually needed for generic drug products or if a formulation is significantly altered during clinical trials. In this master's thesis a pharmacokinetic model (based on a compartmental absorption and transit model, CAT) was constructed and tested to predict relative BA, to assess the risk of bioinequivalency and to probe properties of drugs suitable for the use of the model. Also the errors and uncertainties related to the model were discussed. GI tract physiology, formulation type and drug solubility, dissolution, absorption and elimination rates were taken into account in this pharmacokinetic simulation model. In the model formulation differences were described by dissolution rate constant (Kd) (calculated from experimental dissolution data) and gastric emptying rate (GE) (varies for different formulations). Hence, when integrated with a pharmacokinetic compartment model it was possible to get predictions of concentration-time profiles of different formulations. Generalised rules in BE assessment were used to estimate the risk of bioinequivalency. The resolution power of the model and the errors related to the model was evaluated by theoretical pharmacokinetic simulations. Generally, the simulations suggested that the model predicts the risk in the BE study most accurately when the drug belongs to the class I/III in the biopharmaceutical classification system (BCS) or to the class II when saturation solubility is not the limiting step in the absorption. Used Kd value is valid if dissolution data is accurate (method discriminative). Also, there has to be enough information about the formulation (type, disintegration, excipients). Otherwise it has to be considered if these factors effect on the resolution power. The weaknesses of the simulation models are assumptions. Hence, when exploring the results it has to be estimated case by case, if they affect on model's ability to separate formulations (reliability of the risk assessment and the ability to predict relative BA). This model is useful tool in formulation development and regulatory applications.
  • Kinnunen, Marja (2015)
    Histamine is a monoamine structured signal molecule, which takes part in many functions of living organisms. It was first found in brain approximately 70 years ago. Neuronal histamine regulates for example biological rhythms, energy metabolism and thermoregulation. In the 1980's, H3-receptor was recognized in the brain. Neuronal histamine regulates functions of other transmitters for example gamma-aminobutyric acid, glutamate, acetylcholine, noradrenaline and dopamine. Currently, the interactions of histamine and dopamine are not well characterized. Though, it is known that histaminergic fibers innerviate almost every dopaminergic area of the brain. There are also several H3-receptors in the striatum and in the limbic system. These brain areas are important for the rewarding effect of dopamine. The aim of the experimental part of this Master's thesis was to examine the location of histaminergic and dopaminergic nervous systems in mouse brain by using immunohistochemistry. Primary antibodies that were produced in rabbit (anti-histamine (HA)) and in mouse (anti-tyrosine hydroxylase (TH)), and secondary anti-rabbit and anti-mouse anti-bodies, that were produced in goat and conjugated with fluorophores, were used in the study. The samples were imaged with a confocal microscope. The primary aim was to find out, in which addiction related brain areas, histamine and dopamine cells and fibers are located and how they are situated in relation to each other. H3-receptor antagonists have been shown to decrease the consumption and rewarding effect of alcohol in animal models. Therefore, it was examined if non-imidazole structured H3-receptor antagonist also inhibits the rewarding effect of amphetamine, and if it decreases the locomotor activity induced by amphetamine. JNJ-39220675, a neutral antagonist of H3-receptor, and behavioral paradigm of conditioned place preference (CPP) were used in the experiment. CPP was also used to find out if D2-receptor agonist quinpirole cause reward or aversion. The effect of JNJ-39220675 on quinpirole's place preference and change in locomotor activity was also investigated. The interactions of these two pharmacological ligands were also examined in a separate locomotor activity experiment. C57BL/6J mice were used in all experiments. The results show that there are possible synaptic connections of histaminergic and dopaminergic system in substantia nigra, supramammillary nucleus, dorsomedial hypothalamic area and ventral periaqueductal grey area. Also, histaminergic nerve fibers innerviate to the dorsal striatum, which regulates motor functions, and to the ventral striatum, which is a part of the rewarding system of the brain. Hence, it is possible that histamine regulates the actions of dopa-mine in these brain areas. The behavioral experiments showed that JNJ-39220675 inhibits acutely increased locomotor activity caused by amphetamine, and decreases desensitation of decreased locomotor action caused by repeated dose of quinpirole. However, JNJ-39220675 did not have any effect on the rewarding effect of amphetamine, which causes strong sensitization. Also, JNJ-39220675 did not have an effect on quinpirole's aversive action. It remains to be seen, if H3-receptor is a potential target for new medicines in the treatment of different brain diseases and addiction in the future.
  • Pylkkö, Tuomas (2013)
    It is well known that the central nervous system is a highly isolated tissue. Because of this the physico-chemical criteria to be met by an orally administered central nervous system drug are very strict. This work describes methods that can be used to select drug candidates and screening collections that have a higher possibility of being relevant to central nervous system drug development projects. This work also argues that small molecular space is so vast that it is difficult to imagine any progress without focusing screening collections in some way or another. Given that most available commercial compounds are very similar in some respects, it is very much possible that this presents a bottle-neck for the progress of drug development as a whole. Therefore, research on novel methods for compound production are also evaluated. In addition, this work describes the miniaturization and automation of a previously published ELISA-based assay. This assay measures the activation of a tyrosine kinase receptor (TrkB), expressed in a fibroblast cell line. The receptor, and it's endogenous ligand, Brain-derived neurotrophic factor, have been linked to the mechanism of action of previously discovered medical interventions used in the treatment of depression. Such an assay can be used to discover either small molecule agonists or antagonists acting upon the receptor. These molecules could possibly be clinically relevant in the treatment of depressive disorders and anxiety. It is demonstrated that it is indeed possible to miniaturize and automate the method, making it significantly more suitable for high-throughput screening. The original method was carried out in 24-well plates, transferring the samples to another plate for measurement. The new design uses 96-well plates and performs the entire process on the same plate.
  • Keltto, Katri (2011)
    Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used for the treatment of pain in sheep and swine. Information of correct ketoprofen doses in different animal species is limited. The correct dose cannot be reliably extrapolated based on other species or human. The problem in cases of suspected overdose is knowing whether the given dose was toxic. The objective of the study with sheep was to figure out if the kinetics of ketoprofen is altered by a tenfold overdose, study the effect of the overdose to kidneys and find out a way to diagnose overdose by a simple urine test. The objective of the study with swine was to figure out the bioavailability and pharmacokinetics of ketoprofen after oral, intramuscular and intravenous administration. The most important variables were AUC0-_, Cmax and Tmax. Bioavailability was calculated based on intravascular administration. 30 mg/kg ketoprofen was administered intravenously to six sheep. The concentration of ketoprofen in sheep plasma was followed for 24 hours. Pharmacokinetic parameters were calculated afterwards. Blood and urine samples were analysed to detect enzyme markers indicating possible renal failure. The sheep were finished off 24 hours after the administration and the possible damage to kidneys was evaluated from histological samples. Ketoprofen was also administered to eight swine. The doses were 3 mg/kg of oral, intramuscular and intravascular, and 6 mg/kg of oral ketoprofen. The study was performed as a randomized, cross-over study. The concentration of ketoprofen in swine plasma was followed for 48 hours after administration. Pharmacokinetic parameters were calculated and bioequivalence evaluated afterwards. The in vivo -studies of both of the studies as well as the histological study of the kidneys, and the urine and blood analysis except for the analysis of ketoprofen concentration, were carried out by the researchers of the Faculty of Veterinary Medicine. Plasma ketoprofen concentrations were measured by high-performance liquid chromatography (HPLC). Drug concentration and pharmacokinetic analysis were carried out in the Faculty of Pharmacy. The tenfold dose of ketoprofen was toxic in sheep. Serum concentrations of urea and creatinine increased. Histological samples revealed acute tubular damage. Many urine enzyme concentrations increased. The rise of urine lactate dehydrogenase (LD) concentration was most significant and earliest. LD appears to be a potential marker of a toxic ketoprofen dose. Compared with the therapeutic dose, overdose did not affect ketoprofen elimination rate from plasma, so the kinetics of ketoprofen was not altered. AUC- and Cmax -values were over tenfold compared to the therapeutic dose, so the values did not rise linearly as the dose reached a toxic level. Bioequivalence of ketoprofen in swine was not observed between different routes of administration. The bioavailability was excellent in all routes of administration. Tmax was slightly over one hour after administration. Cmax and AUC were 5,1 mg/l and 32 mg l-1 h after oral 3 mg/kg dose and 7,6 mg/l and 37 mg l-1 h after intramuscular dose. The increases in AUC and Cmax were linear between the different dosages of oral ketoprofen. The difference of the elimination rates between oral and intravascular administration was statistically significant. Ketoprofen distribution volume and clearance did not differ significantly between different routes of administration.
  • Taavitsainen, Eveliina (2017)
    Chlamydia pneumoniae is an intracellular human pathogen that causes respiratory infections such as pneumonia. Antibodies have been found in serological samples worldwide and most likely every person gets an infection at least once in lifetime. In particular, persistent C.pneumoniae-infection has been associated with multiple chronic diseases such as atherosclerosis, asthma and neurological diseases. C.pneumoniae has a unique two-stage life cycle with two morphological forms; elementary body and reticulate body. In addition, the bacterium has a chronic persistent form. Persistent infection is very typical. Persistent infection can be produced in many ways in vitro, but it has been also found that C.pneumoniae is spontaneously transformed into persistent form in macrophages and monocytes. The aim of this study was to investigate the effect of anti-chlamydial compounds previously identified in the research group on the persistent infektion of C.pneumoniae. For the study, the growth of the bacteria was monitored by qPCR in different cell lines and the compatibility of the compounds with the used persistence model was studied. Four different cell lines were used in the study; HL epithelial cells, Raw264.7 macrophages, THP1 monocytes and macrophages. The effect of compounds on the used cell line was first examined by viability assays. For further studies, C.pneumoniae growth was studied in different cell lines. An qPCR method was set up and used to monitor C.pneumoniae genome copy numbers in infected samples. Based on the growth curves, the measurement points were determined for further studies. Finally, the effect of suitable compounds on C.pneumoniae infection was investigated in epithelial, monocyte and macrophage cell lines. From the investigated compounds, Schisandra chinensis-lingnans were selected for further studies with Raw264.7 cells. The genome number wa not found to decrease compared to the after schisandrin or schisandrin B treatment. In the experiment of the growth of the bacterium, schisandrin-treated samples showed that the genome number of bacterium would be re-grown. This may potentially mean the persistent infection change back to the active form, whereby the bacterium resumed proliferate in the host cell. Based on the results of this study, schisandrin may be considered a potential compound for further studies and a possible model compound for the development of compound against C.pneumoniae infection. However, further studies on the effect of the compounds on persistent infection are needed.
  • Tyni, Oona (2023)
    Verensiirtoja tarvitaan monissa erilaisissa tilanteissa, kuten akuutissa verenhukassa, leikkauksissa ja sairauksien hoidoissa. Verivalmisteiden laajan käytön takia, on tärkeää varmistaa veriturvatoiminnalla niiden laatu sekä turvallisuus. Olennainen osa verivalmisteiden laadunvalvontaa on seuloa veren välityksellä leviäviä taudinaiheuttajia. Suomessa veren välityksellä leviävien tautien leviämisen riski on lähes olematon tarkan laadunhallinnan ansioista. Verenluovutusajankohtana oireettomat taudit aiheuttavat kuitenkin riskin laadunhallinnalle. Koska krooninen Chlamydia pneumoniae -infektio voi olla oireeton, on tärkeää tutkia taudin kykyä levitä verivalmisteiden välityksellä. Tätä ennen on kuitenkin tutkittava, löytyykö verivalmisteista edes kyseistä bakteeria. C. pneumoniae on gram-negatiivinen solunsisäinen bakteeri, joka aiheuttaa ihmisillä erilaisia akuutteja hengitystieinfektioita, kuten keuhkokuumetta, nielutulehdusta ja sinuiittiä. Vaikka suurin osa tartunnoista on oireettomia tai lieväoireisia, voi infektio muuttua hoitamattomana krooniseksi. Akuutissa infektiossa C. pneumoniae infektoi pääasiassa keuhkojen epiteelisoluja sekä alveolaarisia makrofageja. Infektion pitkittyessä bakteeri voi levitä muihin elimistön soluihin valkosolujen välityksellä. Tämä bakteerin kyky aiheuttaa kroonista infektiota sen muuttuessa persistenttiin muotoon tekee bakteerista hyvin menestyvän. Tämän tutkimuksen tavoitteena oli selvittää, kuinka paljon C. pneumoniae -bakteeria esiintyy suomalaisessa luovutusveressä. C. pneumoniae -bakteerin DNA:n tunnistamiseen kokoverestä käytettiin kolmea eri PCR-menetelmää: kvantitatiivista PCR:ää, sisäkkäistä PCR:ää ja digitaalista pisara PCR:ää. Työn ensimmäinen vaihe oli suunnitella ja optimoida nämä kolme PCR-menetelmää. Menetelmien pystyttämisen jälkeen 40 verinäytettä tutkittiin kyseisillä PCR-menetelmillä. Lisäksi samoista verinäytteistä määritettiin C. pneumoniae spesifisen vasta-aineen, immunoglobuliini G:n, määrät ELISA-immunomäärityksellä. Verinäytteitä tutkittaessa C. pneumoniae -bakteerin esiintyvyys suomalaisessa luovutusveressä oli hyvin pieni. Vain kahden näytteen (2/40) epäiltiin olevan mahdollisesti positiivisia, sillä nämä antoivat mahdollisia positiivisia tunnistuksia vähintään kahdessa PCR-ajossa. C. pneumoniae spesifisten IgG vasta-aineiden esiintyvyys oli suurempi; näytteistä 50 % oli igG positiivisia. IgG vasta-aineiden esiintyvyyden ei todettu korreloivan iän tai sukupuolen kanssa. Aiemmissa tutkimuksia C. pneumoniae -bakteerin esiintyvyys luovutusveressä on vaihdellut 7–46 %:n välillä. Bakteerin esiintyvyyden jäädessä hyvin alhaiseksi on mahdollista, että PCR-menetelmien detektioherkkyys ei riittänyt tässä tutkimuksessa tunnistamaan toistettavasti mahdollisia positiivisia näytteitä. Näin ollen PCR-menetelmien lisäoptimointi olisi tarpeen.
  • Ukkonen, Hanna (2012)
    In medicines APIs are most oftenly at solid form. Crystal forms are more stable than amorphic solid form. Crystals are hold together by intermolecular interactions. Strongest and most common intermolecular interaction in crystals is hydrogen bond. Crystallisation is affected by thermodynamics and kinetics. Same phenomena effect also dissolving of crystals. New APIs often have a poor water solubility which makes them difficult to use. Cocrystals are one way to improve physical characteristics of molecules and most of all solubility. In co-crystals two different solid molecules are crystalliced in a same crystall lattice. Itraconatzole is an API with a poor water solubility. Itraconatzole can form cocrystals with many bicarbocsylicacids. The smallest bicarbocsylicacid that had formed co-crystal with itraconazole is malonic acid. The purpose of the experiment was to grow itraconazole malonic acid co-crystal, which is big enough for single crystall x-ray diffraktion. With SXRD it is possible to find out how molecyles are placed in a crystall lattice. For SXRD the single crystal is not allowed to have a single mistake in its lattice. Itraconazole and malonic acid were dissolved to 1,2-dichloroethane-2-butanone and tetrahydrofurane-chloroform for growing up a single crystal. Crystallisation methods used were evaporation of solvent, adding antisolvent and cooling down of solution. Formed crystalls were analysed with DSC, raman, XRD and TGA. It was succeeded to crystallise itraconazole malonic acid co-crystals with used methods. The formed crystalls were needlelike and packed in small drifts. Any crystall big enough for SXRD was not succeeded to grow up with the methods used. Growing up a bigger co-crystal needs the use of new methods or optimation of the ones used in this experiment.
  • Neuvonen, Janina (2019)
    Flowability of powders is in critical role when manufacturing the most popular dosage forms, tablets and capsules, of pharmaceutical industry. Re-formulation is expensive and time-consuming, so it is important to determine powder flow properties at the initial stage of drug development prior to tabletting and encapsulation processes. There are many different methods, like shear cell, flow through an orifice and bulk and tapped density, to examine powder flowability. Despite the methods, the most reliable means of examining powder flowability is often empirical. In early stages of drug development, it would be good to have faster, more reliable and cheaper methods to examine powder flowability. FT4 Powder Rheometer is a relatively new flowability characterization technique. The aim of this study is to find out whether the library created using the FT4 Powder Rheometer methods makes it possible to characterize the rheological properties of solids in the early stages of drug development. In addition, the aim is to investigate whether FT4 Powder Rheometer methods can predict the success of masses in tableting and encapsulation processes. The information gained from the research can be used in the future, for example, in continuous processes, because flowability plays an important role, especially in the supply of raw materials to the process, which is the most important division of continuous processes. To the library were selected for particle size and shape 15 different types of material. These materials were subjected to five different FT4 Powder Rheometer basic test methods. In addition, the particle size and shape of the materials and the flow through an orifice and the bulk and tapped density were determined to support the results of the powder rheometer. The principal component analysis was used to process the results. As the tablet and capsule masses examined, the masses of a previous study were utilized. Those masses were tableted and encapsulated in that previous study. These tablet and capsule masses contain a variable amount of cohesive drug substance. FT4 Powder Rheometer methods provide more complex information about materials and their behaviour than conventional flowability test methods. From the powder rheometer parameters pressure drop, compressibility and specific energy distinguish the cohesive and the non-cohesive materials, because the cohesive materials with these parameters obtain clearly higher values than non-cohesive materials. Additionally, the cohesion of FT4 Powder Rheometer shear cell test mainly distinguishes highly cohesive materials from other materials. The flow rate index makes it possible to separate the materials to which the change in flow rate particularly affects. Fluidizing materials, due to the air flow, are distinguished by the aeration test. Avicel PH-102 could be used as a rough limit value for well and poorly flowing materials in the created library (excluding the aeration and shear cell test). Stability index -, flow rate index -, specific energy -, pressure drop -, and compressibility-results of the FT4 Powder Rheometer correlated to the proportional proportion of the cohesive drug in the mixture. These parameters could possibly be used to distinguish mixtures containing the cohesive material. Additionally, specific energy, compressibility, pressure drop, basic flowability energy, stability index and flow rate index correlated with the weight variation of the tablets. With these parameters one could possibly assess the tabletability of the mixtures. A much larger library is needed to evaluate and predict the rheological properties of new materials. FT4 Powder Rheometer can possibly be used to predict the tableting success of tablet and capsule masses. This would be interesting to look more extensively, for example as part of a library. Additionally, it would be good to investigate whether the results of powder rheometer correlate to continuous production.