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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(2013)The pet medication industry is growing but there are still challenges especially in feline medication. Palatable flavours, efficient taste masking technologies and easily administrable dosage forms are needed to facilitate feline medication. Based on the literature review, there is only little information about cat's preference to individual flavours. The methods for palatability testing should be improved to achieve reliable results. Most common taste masking technologies are flavouring and tablet coating. In experimental section different flavours for taste masking were studied. Five main flavours were selected: phenylalanine, leucine and methionine as possibly good flavours and arginine and denatonium benzoate as bad flavours. In preformulation experiments tableting characteristics, thermal behaviour and crystal structure of flavours were analysed. The aim was also to study their possible incompatibilities with tablet excipients. The main compatilibility study method was X-ray powder diffraction (XRPD), but differential scanning calorimetry (DSC) was also used. Excipient povidone (PVP) was incompatible with nearly all of the main flavours. The use of lactose as an excipient was excluded because of the risk of the Maillard reaction. In tableting studies a tablet mass containing microcrystalline cellulose (MCC), calcium hydrogen phosphate dihydrate, mannitol, hydroxypropyl cellulose (HPC), crospovidone, talc and sodium stearyl fumarate was produced. Minitablets of diameter 3 mm without any flavours were compressed. Also minitablets with flavours phenylalanine and denatonium benzoate were compressed. Minitablets complied with the European Pharmacopoeia tests for uniformity of mass, disintegration and friability. However, characterization and handling of minitablets was found to be challenging due to very small size of the tablets. Minitablets are a promising technology for facilitating feline medication in the future.
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(2010)The purpose of this study was to describe cat owners' problems that relate to cat medication, especially from the drug formulation point of view. Oral, topical, eye and ear administration routes were included into study. There are few compliance and palatability studies made for cats and dogs in Finland and abroad, but this kind of descriptive study relating different drug formulation has never been done before. This study was carried out as Internet survey questionnaire study and it was addressed to cat owners who visited in academic veterinary hospital for small animals and those municipal and private veterinary offices that were randomized into the study. Additionally, the survey study was addressed to cat owners who had medicated their cats during January-March 2010. Those cat owners were contacted through Internet discussion sites. In the veterinary offices the office staff selected the proper candidates for the study and distributed invitations to participate. For distributing invitations the main criteria was that the cat owner received veterinary medication prescription or got directions for using some medication in cat. 59 answers were received in the study and 84 % of all formulation were administered via oral route. The products were antimicrobial and paracite medicines, cardiovascular and anti-inflammatory medicines. Based on the study results most of the problems were related to oral and ear administration routes. Cat showed low compliance and unwillingness to take pills and capsules because of the unpleasant smell, taste and mouth feel of the product. Tablet and capsule form medicines caused problems to the owners, because it was often necessary to adjust the dose by splitting and cutting half the tablet. This made it difficult for owners to follow given medication instructions. The consistency of liquid medicine forms was described sticky and package material thick and stiff. Because of these factors cat owners had difficulties to evaluate the amount of drops to administer to cats ear or eye and the amount remaining in the medicine bottle. According to the study results there is a need for palatable and easily administered medicines that will be taken readily by cats. It should also be possible to adjust to dose as described. The survey questionnaire is a convenient study method for descriptive purposes and it should be carefully considered what kind of sampling method to use and how to carry out the sampling in practice.
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(2013)Voltage-gated sodium channels play an essential role in the function of the nervous system as they are responsible for producing action potentials. Abnormal activity of sodium channels is in connection to several diseases such as epilepsy and chronic pain. Voltage-gated sodium channel blockers which are selective towards a specific isoform could provide more efficient and better tolerated drugs to treat these diseases when compared to the drugs used today. Clathrodin is an alkaloid isolated from Caribbean sea sponge Agelas clathrodes. Bioactivity studies have shown that clathrodin changes the function of voltage-gated sodium channels. The aim of this study was to synthesize two kinds of structure analogs of clathrodin and study their structure-activity relationship towards different isoforms of voltage-gated sodium channels. The study is part of the MAREX project (Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications) funded by the European Union. Intention of the project is to find new bioactive compounds in marine organisms. A four-step route was developed for synthesizing 2-aminobenzothiazole analogs. A three-step route was developed as well but the last step seemed to be problematic for some of the compounds. The three-step route provided new compounds as intermediates and some of them were sent to tests for activity. Synthesis of 1H-pyrrole-2-carboxamide analogs of clathrodin failed. 4,5-dihydrooxazole was recognized as a problem as it was formed as a result of a cyclization reaction when bromination was tried on the intermediate. The formed structure was used in synthesizing 2-(1H-pyrrol-2-yl)-4,5-dihydrooxazole analogs of clathrodin. These reactions failed to give any final products which could have been tested for activity. Eight synthesized compounds were sent to tests for activity. Results were received from two of them and they showed no activity towards the voltage-gated sodium channels in 10 µM concentrations. Discussion about structure-activity relationship is not possible based on two compounds only.
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(2020)The national legislation, based on EU Directive 93/42, has regulated the high-risk medical devices in Europe to this day. It requires that in order to enter the market, the device must be safe, suitable for the intended use and acceptable in performance. The demonstration of clinical efficacy is not required. The information on which clinical evidence is based, is not publicly available, as clinical evaluation data and the results of a clinical trial are not required as a condition of market access in Europe. This has given the opportunity for manufacturers for faster and more cost-effective pathway to bring the medical devices to market in Europe. This has boosted the activity of device industry in Europe. However, the weaknesses of European legislation are considered to be one of the reasons caused the large-scale device scandals (lack of safety and effectiveness) in the early 2000s. As a result, a new EU Regulation 2027/745 on medical devices has been created and will enter into force in all Member States in May 2021. The aim of this study was to create an overview of the clinical evidence on high-risk medical devices marketed in Europe and how the issue has been investigated. A systematic literature review was used as the method in this study. The challenge was that there was lack of material available on the subject in question. This is probably due to the limited availability on clinical information of marketed devices, as a public database (Eudamed) does not exist yet in Europe and the device manufacturer may not publish the results of clinical studies. This issue has been investigated by using some reimbursement assessment decisions could be found from few European countries. The level of clinical evidence of devices in the United States has been extensively investigated. Medical devices marketed in Europe have been submitted for registration to United States, so information on European devices can be found in United States public sources. This information will provide a stronger insight of the level of clinical evidence regarding the devices marketed in Europe and thus the publication has been justified to be included in this study. According to the information obtained from this study, the clinical evidence of high-risk medical devices is mostly incomplete and of poor quality. This has negative effects on physicians making treatment decisions, patients using the devices, as well as device manufacturers. Clinical trial methods do not fully comply with the gold standard and the use of other methods is not clearly justified. The requirements for new devices will be significantly tightened and the clinical evidence of already approved devices will need to be updated due to the new device regulation. Clinical data will be publicly available in Eudamed database in the near future. Guidance from Notified Bodies and Authorities regarding alternative methods for clinical trials expected to be also clarified. New requirements of clinical evidence will increase manufacturer´s costs. It may also be the case that, clinical evidence updates of current devices cannot be implemented from a safety point of view. It is likely that important devices will exit the European market and the industry will suffer. An agreement should be reached together with authorities and industry to ensure self-sufficient European device manufacturing and the promptly availability of vital devices for patients.
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(2013)During the past few decades the focus of the pharmacy profession has shifted from medicinal products towards ensuring the welfare of the patient. The concept of pharmaceutical care emphasizes that the role of the pharmacist is to ensure the quality and safety of pharmaceutical therapy in collaboration with the patient. The concept of clinical pharmacy, on the other hand, highlights that the pharmacist should take the responsibility of the efficiency, safety and cost efficiency of the patient's pharmaceutical treatment together with other health-care professionals. Patient centered pharmacy services have been increased in Finnish hospitals and health care-centers during the last 10 years, for example, in the form of pharmacy services provided on the wards. Previous studies have shown that Finnish hospital pharmacists want to develop and increase clinical pharmacy services in hospitals but feel they are not competent enough to manage them. To develop and increase the number of clinical pharmacy services it is important to ensure the pharmacy professionals have support to their continuing professional development. The General Level Framework (GLF) has been developed in the UK to support the professional development of pharmacy professionals and its value has been shown in various studies. The aim of this study was to give information of the state of Finnish hospital pharmacy and its development needs as perceived by Finnish hospital pharmacists, and to investigate how the GLF can be utilized in Finnish hospital pharmacy. The study was conducted using two different research methods: a semi-structured interview was designed to investigate hospital pharmacists' perceptions of hospital pharmacy, it's development needs and utilization of the GLF; in addition, hospital pharmacists selfassessed their clinical pharmacy related competencies using the GLF. All of the participants of the study were participants of a clinical pharmacy course by University of Helsinki. In total 11 hospital pharmacists took part in the interview. Also 41 pharmacists self-assessed their competencies in clinical pharmacy using the GLF: eight of them completed the self-assessment twice with a six month period between the assessments. The interviewed pharmacists felt that the pharmacy curriculum should focus more on the skills and competencies needed in hospital pharmacy. On the other hand, they felt that the tasks of hospital pharmacists did not necessarily allow them to use their actual knowledge of pharmacy. They perceived that the future of hospital pharmacy lies in services of clinical pharmacy, although they felt that they were not competent enough to manage them. The GLF self-assessment showed that the clinical competencies of the participants were average, and there was no change in the competence of the participants during the six month period. However, the interviewed pharmacists felt that the GLF can be used as a tool for support the hospital pharmacists' professional development and continuing professional development in clinical pharmacy. They also perceived that there is a need for further studies on the clinical pharmacy services and their benefits, and that the task distribution of health care professionals in hospitals must be re-considered. With these actions, the challenges hindering the development and increase of clinical pharmacy services in Finnish hospitals could be overcome. They described that the greatest challenges to overcome were prejudices against pharmacist working on the wards and a lack of resources. In order to develop and increase clinical pharmacy services in Finnish hospitals and other health-care organizations further reseacrh on the benefits of clinical pharmacy should be conducted. It must also be ensured that all health-care professionals and decision makers are aware of the studies already made about clinical pharmacy and its benefits. The skill-mix of health care professionals taking part in a patient's treatment must be reconsidered in order to ensure that the patient receives the best, most efficient and safest possible medicinal care. The GLF can be used as a tool to define the role of a clinical pharmacist in Finland. There is a need for more clinical pharmacy education so that Finnish pharmacists can feel competent enough to manage clinical pharmacy tasks. The GLF can be used as a tool to support the professional development and continuing professional development also in Finland.
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(2010)The major problem in cancer treatment is toxic side effects of the chemotherapy. Typically less than 1 % of the administered free drug reaches target cells while the rest damages non-diseased cells. Toxic side effects often limit dose escalation of anticancer drugs which leads to incomplete tumor response, early disease relapse and possible the development of drug resistance. Liposomes can be targeted in cancer tissue with passive or active targeting. In passive targeting the liposomes accumulate in abnormally formed cancer tissue through the process of extravasation and enhance the concentration of liposomal drug in solid tumor. To further improve the anticancer efficiency of passive targeted liposomes is to couple a targeting ligand to the surface of the drug carrier (i.e. active targeting). The ligand specifically binds to a surface epitope on the target cell leading to the accumulation of the liposomal drug inside the tumor cells. The aim of this study was to investigate the cytotoxicity of targeted immunoliposomes. In experimental part the liposomes were constructed using cetuximab (C225, Erbitux®) antibody and evaluated for specific cellular uptake and cytotoxicity in vitro. Cetuximab antibody is specific and selective inhibitor of HER-1 -protein (ErbB-1, EGFR, epidermal growth factor receptor). HER1 -protein is frequently expressed in high levels in human carcinomas (for example in lung and colorectal cancers, head, neck and breast cancers and in pancreatic, ovarian, prostate and bladder carcinomas). Specific immunoliposome uptake and cytotoxicity were studied in SKOV-3cells (ovarian adenocarsinoma cell line) which overexpress the EGF -receptor. Monkey kidney epithelial cells (CV-1) were used as a control cell line which represents non-diseased cells. Active targeting and cellular uptake of liposomes were investigated in cell uptake studies. Non-targeted pegylated liposomes were used as control liposomes. Specific binding of the cetuximab antibody to EGF -receptor was noticed in competition studies. The in vitro cytotoxicity of doxorubicin containing immunoliposomes was studied with Alamar Blue® cell viability assay. Liposome size was determined at intervals of about two weeks during the experimental part. In conclusions, antibody targeted immunoliposomes showed greater cellular uptake and cytotoxicity in EGFRoverexpressing target cells (SKOV-3) than the corresponding non-targeted liposomal drug. Immunoliposomes showed greater cytotoxicity after five days incubation, which can be a consequence of liposome formulation and slow rate of release of doxorubicin. In contrast, antibody targeted liposomes did not show specific cellular uptake or cytotoxicity in CV-1 control cell line. In clinical cancer therapy actively targeted liposomes could improve the therapeutic effectiveness of the liposomal preparations. Many studies have shown that ligand-bearing liposomes will selectively bind to target cells in vitro, but only few studies have shown the possibility in vivo.
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(2011)In cancer therapy nanocarriers can be loaded with therapeutic or diagnostic agent and nucleic acid sequences. Targeting moieties can be attached to the nanocarrier for passive or active targeting or carrier can be labeled with radioactive isotope for imaging or radiotherapeutic purposes. Enclosing the drug in a nanocarrier may improve the molecule's physico-chemical properties, bioavailability, reduce side-effects, longer the circulation time and dosing interval, and improve uptake in the target tissues. Thus, the efficacy of chemo- or radiotherapeutic could be improved. It may lead to improved survival. Pro gradu investigates nanocarriers' role in cancer therapy. Regardless of research, continued for decades, only 2 (Europe) or 3 (United States) nanoparticle formulations are approved in cancer therapy. Major limiations are inefficient uptake in the target tissue, immunogenicity of nanoparticles and targeting ligands, and lability. The aim of this study was to investigate pre-targeting of 99mTc-labeled, PEGylated and biotinylated liposomes into human ovarian adenocarcinoma cells in vitro and in mice in vivo. Targeting moiety used was biotinylated cetuximab (Erbitux®), an antibody that binds into EGF-receptors, over-expressed in these cells. Pre-targeting was compared to active one step-targeting, with antibody attached to liposomes, and passive targeting. Development of more accurate imaging techniques has accelerated the investigation of targeted nanoparticles. Molecular imaging enables real-time tracking of nanoparticle distribution and metabolic changes. In literature review, SPECT and PET imaging in cancer therapy and nanoparticle research, will be discussed. These imaging methods overcome challenges in sensitivity and accuracy, faced by other imaging methods. In this study we also investigated the biodistribution of 99mTc-labeled liposomes in mice using NanoSPECT-CT-device. Activity in tumor, spleen and liver was quantified using InVivoScope-software and gamma counter and these results were compared. In in vitro study, pre-targeting method was 2,7and 3,5-times more efficient compared to the liposome controls in SKOV3 and SKOV3.ip1 cell lines, respectively. Although, one-step targeting formulation targeted the cells even better. In in vivo -study, i.p.-administered liposomes distributed into tumor more efficiently compared to i.v.-administered liposomes. I.p. pre-targeting method was 1,24-fold more efficient compared to passive targeting, considering the % ID / g tissue. However, %ID/organ in pre-targeting method was 5,9 % whereas passive targeting reached the value of 5,4 %. Conclusively, the difference between pre-targeting and passive targeting was modest. InVivoScope and gamma counter quantification results didn't correlate. Further investigation is needed and protocol optimization required in targetin liposomes into tumors.
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(2022)The medication-use process in hospitals includes several risks which can lead to medication errors. Medication errors can be prevented and managed by adding automation and technology solutions to the medication-use process, such as clinical decision support system (CDSS) integrated into electronic medication administration record (eMAR), unit dose drug distribution system (UDDDS), automated dispensing cabinet (ADC) and bar-code medication administration (BCMA). A closed loop medication management process can be created by integrating different methods and technologies seamlessly. It improves medication safety by decreasing human errors and allows the access to the patient’s medication information in real time. The closed loop medication management process is not yet fully in use in any Finnish hospital, but parts of it have already been implemented. Helsinki University Hospital (HUS) wants to improve the closed loop medication management process by piloting the use of unit dose (UD) bags in the medication- use process and to study its effects on medication safety. The aim of the study was to determine the incidence of the medication dispensing errors and procedural errors, the working time of the nurses, and the nurses' opinions on the current drug dispensing model in a hospital ward before the introduction of the unit dose drug distribution system. The study was conducted as a mixed-method study, which utilized an observational method and an online survey. The data were collected at HUS internal medicine inpatient ward by observing the dispensing of morning medicines for ten days and through an electronic survey sent to the ward’s nurses. The overall incidence of dispensing errors in the current drug dispensing process was 40,1 % (553/1379). Of these, 3,2 % (44/1379) were medication dispensing errors, and after the excluding prescribing errors (n=22), the incidence was 1,6 %. These prescription errors were mainly related to prescribing medications outside the hospital's formulary. In addition, the incidence of procedural errors was 37 % (509/1379). Of the procedural errors, 57 % (292/509) were related to the unattached or missing barcodes and 37 % (186/509) to hygiene deficiencies in drug dispensing. On average, nurses spent 4,5 minutes per patient on medication dispensing and patients had 7 morning medications. The results of the survey also revealed problems related to barcodes as well as hygiene deficiencies, which supported the results of the observations. Significant safety risks, such as unattached barcodes, missing barcodes, and deficiencies in hygiene were identified in the current drug dispensing process. The study indicates that system-based risk management approach is not yet fully understood in hospital units. The root cause of procedural errors should be investigated more and review the ward's instructions with staff, to reduce their incidence in the future. At the end of 2021 a unit dose drug distribution model will be piloted in the ward, which may be one possible way to reduce errors related barcodes and hygiene. In addition, to improve the medication safety, physicians should order medications from hospital's formulary, so that generic substitution would no longer need to be made at the distribution stage. It would be useful to include a category of incorrect orders in the future research setups that investigate medication errors in the dispensing phase to identify such potential risk situations.
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(2018)Obesity is a health problem linked to Western lifestyle and it is becoming more general. The complexity of regulation of eating makes it difficult to regulate body weight, when multiple neural networks and regions of brain have overlapping functions regarding to energy gain. Sufficient amount of energy is vital for individuals surviving in their living environment. Cholinergic messaging in brain is wide and for example nicotine is known for its appetite reducing effect. Anorexigenic proopiomelanocortin neurons mediate the effect of nicotine. In nucleus accumbens and central nucleus of amygdala extracellular levels of acetylcholine rise during meal, which promotes satiety. Satiety inhibits eating behavior between meals. Amygdala is a part of limbic system and in earlier knowledge it was associated only to regulation of memory, conditioning and fear. Nowadays importance of amygdala in eating behavior research is rising, but most of the studies focus on the effect of cue in regulation of eating. Cholinergic messaging is vigorous in the amygdala and is received from opposite areas of brain between basolateral and central amygdala and therefore this master’s thesis examined the effect of cholinergic messaging in amygdala on regulation of eating behavior. C57BL/6JRcc male mice were stereotaxically implanted with guide cannulas either in the basolateral complex of amygdala (n=10) or central nucleus (n=13). After recovering and habituation to automated pellet dispenser mice were treated with nicotinic and muscarinic receptor agonists and antagonists and eating behavior was recorded for six hours. Nicotine, administered to central and basolateral part of amygdala, lowered the number of pellets mice ate. In central nucleus effect was dose dependent. Mecamylamine had time related effect on eating behavior in basolateral amygdala, but dose dependent response was seen only in cumulative results. Oxotremorine was the only compound which created statistically significant interaction between time and dose. Result was seen in both groups. Scopolamine reduced eating behavior in central nucleus and dose dependency was seen. In basolateral complex scopolamine had time related effect, similar to mecamylamine. The results suggest that amygdala regulates eating behavior even without cue.
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