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There are certain characteristics in children’s medication process, such as weight or body surface area-based drug dosing and off-label use of medications, that expose children to medication errors. Small children especially are prone to physical injuries resulting from medication errors. High-alert medications bear a heightened risk of causing significant, even life-threatening harm to a patient when used in error. The aim of this study was to promote children's medication safety by identifying medication errors and contributing factors to errors associated with the use of high-alert medications in pediatric medication process in a hospital environment. The data of this retrospective register study consisted of voluntary medication error reports (HaiPro) made in the pediatric and adolescent units at Helsinki university hospital (HUS). ISMP's (Institute for Safe Medication Practices) list of high-alert medications in acute care settings was used to limit the data. The data was analyzed by using both quantitative and qualitative methods. The aim of the quantitative analysis was to report the frequencies (n) and proportions (%) of high-alert medications and routes of administration and the aim of the qualitative analysis was to identify the types of medication errors and contributing factors in the data. ISMP’s high-alert medications accounted for approximately one-fifth (19.7%) of all medication error reports made in pediatric and adolescent units in 2018–2020. Twelve medications and intravenous route covered approximately 65.0% of all high-alert medications and routes of administration mentioned in the data. Medication errors were mostly identified in medication administration stage (43.3%) and administration errors were often preceded by prescribing errors. Dosing errors (20.5%) and documenting errors (16.8%) were the most common medication error types in the data. Errors associated with dosing and infusion rate were most often involved in severe medication errors. The most frequently identified contributing factors in the data were associated with the work situation and conditions, documenting and information transfer or medications. More detailed risk analysis considering high-alert medications and the intravenous medication process and targeting preventive barriers to identified risk areas are recommended in pediatric and adolescent units in the future. Barriers should be planned to cover the entire medication process. Among different types of medication errors, multiple dosing errors and errors during the programming of infusion rate require special attention in the future.

Chronic heart failure is a major worldwide health problem. It is a complex and severe syndrome caused by different kinds of cardiovascular diseases. Cardiac hypertrophy is frequently caused by hypertension and can lead to abnormality in heart contraction, activation of many neurohumoral mechanism and heart failure. The most important neurohormonal mechanisms of heart failure are activation of sympathetic nervous system and the renin-angiotensin-aldosterone system, insufficiently contracting left ventricle, cardiac remodeling and myocyte loss owing to apoptosis. Antihypertensive drug treatment is often used to prevent or decelerate progression of cardiac hypertrophy. Activation of the renin-angiotensin-aldosterone system plays a major role in heart failure. During the past decades angiotensin converting enzyme inhibitors (ACEIs) have been used as firstline treatment of heart failure. ACEI treatment has been shown to reduce mortality associated with chronic heart failure and improve prognosis of the disease. Angiotensin receptor blockers (ARBs) were expected to replace ACEIs in the treatment of heart failure but for the present they are only an alternative to ACEIs. Beta-blocking agents which reduce activation of sympathetic nervous system have established themself as the second most important treatment of heart failure. Diuretics are widely used as the treatment of heart failure but only aldosterone antagonists has been shown to improve prognosis of the disease. Also digoxin is still used in the treatment of chronic heart failure. In the future renin inhibitors, neutral endopeptidase inhibitors, vasopressin antagonists and molecules that affect inflammatory cytokines could potentially be capable of improving the prognosis of chronic heart failure patients. The major object in the present study was to investigate development of left ventricular hypertrophy induced by abdominal aorta banding in male Wistar rats and prevention of hypertrophy by calcium sensitizer levosimendan and angiotensin II receptor blocker valsartan. Also functionality of abdominal aorta banding as a rodent model of cardiac hypertrophy and heart failure was estimated. Abdominal aorta was constricted above the right renal arteries. That leads to pressure overload and increase in cardiac load. Heart response to pressure overload by hypertrophy in the form of wall thickening. 64 rats were assigned to different groups, each having eight rats. Three of the groups were treated with levosimendan with different daily doses (0,01 mg/kg; 0,10 mg/kg; 1,00 mg/kg) and three of the groups were treated with valsartan with different daily doses (0,10 mg/kg; 1,00 mg/kg; 10,00 mg/kg) via drinking water for eight weeks after the surgery. Sham-operated group underwent the same surgical procedures without constriction of the aorta. All the groups were compared to abdominal aorta banded group without any medical treatment. Cardiovascular parameters such as isovolumic relaxation time (IVRT), left ventricle end-systolic (ESD) and end-diastolic (EDD) dimensions, ejection fraction (EF), fractional shortening (FS), cardiac output (CO), stroke volume (SV), interventricular septum (IVS) and posterior wall (PW) thickness were measured eight weeks after the surgery by using cardiac ultrasound. In the present study levosimendan slightly improved systolic function of the heart. Improvement of the systolic function was seen in a tendency to improve ejection fraction and fractional shortening in abdominal aorta banded rats compared to abdominal aorta banded rats without medical treatment. Neither levosimendan nor valsartan affected diastolic function of heart. Diastolic function was measured by isovolumic relaxation time. Neither levosimendan nor valsartan had significant effect on development of cardiac hypertrophy. Cardiac hypertrophy was estimated by measuring heart weight-to-body weight ratio (HW/BW), left ventricular wall thicknesses and left ventricular internal dimensions in systole and diastole. The present study indicates that outflow constriction by aortic banding is clearly a model of cardiac hypertrophy but not of heart failure.

The impact of nanoparticulate drug carriers, especially polymeric micelles, is growing continuously. However, their drug delivery properties in vivo are difficult to predict. In this thesis, the approach of screening a combinatorial library of nano carriers for their drug delivery properties in a high throughput/high content (HT/HC) manner was tested. The library consisted of self-assembling polymeric micelles, using the amphiphilic polymer DSPE-PEG2000. The physicochemical characterization of micelles was focused on size, shape and stability, tested by various methodologies. The micelles were labeled with the fluorescence dye Alexa568 and the combinatorial character was based on labeling with two different Cell Penetrating Peptides (CPP), RGD and transactivator of transcription (TAT), in three molar ratios each. The cytotoxicity concentration ranges and micelle uptake were tested in the ARPE-19 cell line. Intracellular localization was observed by confocal fluorescence microscopy. Quantitative HCS imaging analysis was performed by image cytometry, whereas only the parameter 'micelles spots per cell' was analyzed exemplarily. The quantitative HCS results were not clear and pointed to insufficient optimization of experimental and analytical parameters. The results suggest that HCS could be a suitable method to analyze a nanoparticulate library for its drug delivery properties, requiring careful optimization of experimental parameters. However, the careful characterization of the micellar library is a critical factor in planning and understanding biological experiments.

The aim of this study was to synthesize antimicrobial and anti-biofilm agents using abietic (AA) and dehydroabietic acids (DHAA). Bacterial biofilms are formed when bacteria cells cluster together within a self-produced extracellular matrix. This lifestyle makes bacteria highly resilient to different environmental stresses and conventional antibiotics when compared to single-cell bacteria. Currently, there are no approved anti-biofilm agents as drugs and only a few number of compounds can selectively target biofilms and eradicate them at low concentrations. Potent drugs targeting them are needed. AA and DHAA are abietane-type diterpenoids found in the resin of conifer trees. Antibacterial effects of resin acids have been widely studied, specifically against methicillin-resistant Staphylococcus aureus strain (MRSA). Through the combination of DHAA with different amino acids, Manner et al. (2015) discovered a new class of hybrid compounds that target both planktonic and biofilm bacteria in Staphylococcus aureus. The study group also discovered two of the most potent abietane-type anti-biofilm agents reported so far in literature. This thesis followed the work of the research group by designing and synthesizing additional AA and DHAA derivatives to target bacterial biofilms. Rings A, B and C of the diterpenoid core were modified and 24 derivatives were successfully synthesized. Amino acids were attached to the compounds either before or after ring modification. Standard structural elucidation techniques were used to confirm the structure of the synthesized compounds.

Prolyl oligopeptidase (POP) is a serine peptidase found at high concentrations in the brain, which cleaves short proline-containing peptides at the carboxyl side of proline. POP activity has been shown to differ between healthy people and ones suffering from certain neurodegenerative diseases. Amongst its other functions, it has been shown to accelerate α-synuclein aggregation. Inhibiting the enzyme prevents this acceleration. Many highly potent peptidic POP inhibitors, based on the enzyme’s natural substrates, have been synthesized. One of the problems with many of these peptide-like inhibitors is their inability to penetrate the blood-brain barrier efficiently. Recently, a new surprisingly potent non-peptidic inhibitor based on a novel heteroaromatic scaffold was discovered. There was a need to synthesize analogues of this inhibitor in order to gain a better understanding of the structure-activity relationship for compounds based on the new scaffold. Unfortunately, the heteroaromatic scaffold is relatively unstable without a stabilizing substituent. The aim of this research was synthesizing stable analogues, primarily by replacing the original heteroaromatic ring with other, more stable heteroaromatic rings. It was hypothesized that the activity of the original compound could be retained, as heteroaromatics can often act as bioisosteres of each other. Multiple close analogues containing the new heteroaromatic rings were successfully synthesized and tested. Although they were considerable more stable compared to the original compound, there was a significant decrease in potency. However, the new compounds were not completely inactive, and they provided useful information on the viability and importance of several different substituents. Furthermore, measuring the IC50 value is not enough to evaluate their overall effect on POP, since the inhibition of the proteolytic activity of POP does not seem to correlate with the inhibition of its other functions. Further investigation and development of the new compound series is needed.

Seas are one of the most biodiverse and species-rich areas on the planet. Many of the underwater species are yet to be found and identified. The marine based drug discovery and the clinical pipeline of marine compounds have increased lately. Thus, there is a strong believe that the marine-derived compounds will provide new pharmaceutical lead compounds. Marine sponges are one of the most studied marine species. Sponges can be found in shallow and deep waters all over the world. Pseudoceratina purpurea is a Verondiga order sponge that is known to be a source of bromotyramines. Bromotyramines are tyramine derivatives that have represented biological activity including cytotoxity, antivirality and antimicrobial effects. Purpurealidin E is a bromotyramine that has been identified from Pseudoceratina purpurea. Purpurealidin E hasn't showed remarkable biological activity by itself, but it can be used as starting point for synthesis of novel bromotyramine derivatives. By forming an amide bond between carboxylic acid and primary amine of purpurealidin E, new bromotyramines can be synthesized. In this master's thesis, purpurealidin E was successfully synthesized. Total amount of 11 novel bromotyramine derivatives were synthesized by amide coupling. Three of the new bromotyramine derivatives and purpurealidin E were purified and their biological activity against hepatitis C virus (HCV) was evaluated. Purpurealidin E did not show any antiviral activity, but all the three compounds showed potential biological activity against HCV. This work can be considered to a continuum to the now ended MAREX project (Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications).

Interindividual variability in drug responses can complicate the determination of drug doses and increase drug-related risks. The variability can be caused by pharmacokinetics or pharmacodynamics of drug. One significant factor giving rise to the variability in the pharmacokinetics is the genetic polymorphism of cytochrome P450 (CYP) enzymes. CYP2C19 and CYP2D6 are highly polymorphic enzymes and many of their polymorphisms are well-known. For both genes there exist null alleles producing the enzyme with complete lack of function and alleles producing increased enzyme activity. Additionally there are alleles of CYP2D6 leading to partially deficient enzyme function. Based on the genotype of the CYP gene individuals can be divided into four phenotype groups describing the enzyme activity: poor, intermediate, extensive and ultrarapid metabolizers. According to the clinical observations the pharmacokinetics of CYP2C19 and CYP2D6 substrates in the individuals genotyped as poor metabolizers often significantly differentiates from the pharmacokinetics in the individuals belonging to other phenotype groups. Between the other phenotype groups the pharmacokinetic variability caused by the genotype seems to be often covered by other reasons causing variability in the pharmacokinetics. The pharmaceutical industry could benefit from methods that could predict the interindividual variability in the drug responses before the clinical studies. The pharmacokinetic variability caused by the genetic polymorphism of CYP enzymes has been predicted with different kinds of static and dynamic physiologically based pharmacokinetic simulation models. The models have taken the CYP genotype into account by non-substratespesific or substratespesific methods. The models have succeeded to predict the clinically observed interindividual variability in the pharmacokinetics of substrates. The goal of this study was to find out if in vitro metabolism data obtained with human liver microsomes genotyped for CYP2C19 or CYP2D6 could be used to predict the interindividual variability in the pharmacokinetics of drugs. The effect of polymorphism on metabolism was examined by incubating the substrates with microsomes with different CYP2C19 or CYP2D6 genotypes. S-mephenytoin, omeprazole and Y1 (compound developed by the pharmaceutical company Orion Oyj) were used as substrates for CYP2C19. Neither the rate of metabolism of S-mephenytoin nor omeprazole appeared to be dependent on the CYP2C19 genotype, with the exception of the poor metabolizer genotype. Use of microsomes genotyped for the other CYP2C19 phenotypes to obtain predictive in vitro metabolism data might therefore not be reasonable. More significant dependence of the Y1 metabolism on the CYP2C19 genotype could not be completely excluded. When examining the effect of polymorphism on non-selective metabolic reactions, the activity of metabolizing enzymes other than the polymorphic enzyme should always be taken into consideration: in this study, CYP3A4 activity biased the results initially achieved with omeprazole and Y1. Dextromethorphan and bufuralol were used as substrates for CYP2D6 and their rates of metabolism correlated well with the CYP2D6 genotype. So microsomes genotyped for CYP2D6 could possibly be used to obtain predictive in vitro metabolism data. If genotyped microsomes are to be used in the pharmaceutical industry to predict the interindividual variability in the pharmacokinetics, factors increasing reliability of the results should be considered first and more studies should be conducted.

Lääkkeiden saatavuushäiriöt ovat yleistyneet maailmalla ja Suomessa viimeisten 20 vuoden aikana lisäten lääkealan toimijoiden työmäärää sekä kustannuksia. Saatavuushäiriöt aiheuttavat myös vaikeuksia potilaiden hoidon toteuttamiseen, tietyissä tilanteissa hoito saattaa joutua katkolle tai joudutaan käyttämään vaihtoehtoista lääkitystä, mikä saattaa heikentää potilaan saaman hoidon laatua. Tämän tutkimuksen tavoitteena oli tutkia kirjallisuuden perusteella syitä saatavuushäiriöiden taustalla. Toissijaisena tavoitteena oli löytää mahdollisesti toimintamalleja, mitkä mahdollistaisivat saatavuushäiriöiden määrän vähenemisen tai vaihtoehtoisesti vähentäisivät niiden vaikutuksia potilaiden hoitoon. Tutkimus tehtiin systemoituna kirjallisuuskatsauksena. Tutkimukseen valikoitui mukaan yhteensä kaikkiaan 24 sisäänottokriteerit täyttävää artikkelia. Kirjallisuushaku suoritettiin 20.10.2020 Sopusi ja Pubmed -tietokannoista. Kirjallisuushaku rajattiin koskemaan ajanjaksoa 2000–2020. Tietokantojen lisäksi kirjallisuutta haettiin manuaalisesti löydettyjen artikkeleiden lähdeluetteloista. Kirjallisuushaulla löydettiin yhteensä 2334 artikkelia ja duplikaattien poiston jälkeen jäljelle jäi 1783 artikkelia. Ensin artikkelit käytiin läpi otsikon sekä abstraktin perusteella ja viimeisessä vaiheessa koko tekstin perusteella. PRISMA-listaa käytettiin soveltuvin osin apuna katsauksen laatimisessa. Tähän systemoituun kirjallisuuskatsaukseen mukaan valituista julkaisuista 10 oli alkuperäisiäjulkaisuja artikkeleita ja 14 katsausartikkeleita. Alkuperäisistä tutkimusartikkeleista suurin osa (n=7) oli kvantitatiivisia tutkimuksia ja näistä neljä käsitteli saatavuushäiriöitä Yhdysvalloissa. Kvantitatiiviset tutkimukset olivat kaikki viranomaisten ylläpitämistä rekistereistä tehtyjä tutkimuksia. Laadullisia tutkimuksia alkuperäisissä artikkeleissa oli kolme, nämä olivat toteutettu puolistrukturoituina haastatteluina tai avoimina kyselyinä lääkealan toimijoille Systemoidun kirjallisuuskatsauksen tulosten perusteella saatavuushäiriöiden syyt voivat vaihdella eri markkinoiden välillä. Saatavuushäiriöiden taustalla olevien syiden teemat kuitenkin vaikuttivat tutkimuksen perusteella olevan hyvin samankaltaisia riippumatta markkinoista. Yleisimpinä syinä saatavuushäiriölle olivat tuotantoon liittyvät ongelmat, regulatoriset toimet sekä ekonomiset ratkaisut. Tulosten perusteella ensisijaisena ratkaisuna saatavuushäiriöiden vaikutusten minimointiin olisivat lääkkeiden valmistajien tarpeeksi ajoissa antamat ilmoitukset alkavasta saatavuushäiriöistä.

For pediatric patients, it is often necessary to resort to off-label use of available commercial products. This may require manual modification of the preparations, which may result in reduced dose accuracy. In the past, there have been discussions about the potential of 3D printing technologies for on-demand manufacturing of medicines in hospitals. Printing technologies can be used to tailor medicines to the individual needs of patients. This could be a possible solution to the lack of commercial products for pediatric patients, for example. Semi-solid extrusion is a printing technique that could potentially be used in the future in hospitals. This study aims to design the simplest possible excipient composition for a printing material for semi-solid extruded preparations for pediatric patients. The finished products will be examined to determine the type of products achieved with this printing method and excipient composition. In addition, the suitability of semi-solid extrusion in a hospital environment will be observed and evaluated. Printing was performed with a pneumatic bioprinter. The desired formulations could not be prepared with a printing material containing only a gel former (poloxamer 407) and a solvent (water). Therefore, a filler (microcrystalline cellulose) was added to the printing material to improve the mechanical strength of the preparations. The model drug used in the study was warfarin sodium and the target strengths of the preparations were 0.1 mg, 0.5 mg and 1.0 mg. The preparations were dried at room temperature for 22-23 hours. The tablets produced in the study were small (diameter less than 7 mm, height less than 2 mm) grid-structured preparations. The method was successful in producing tablets of uniform mass. For all strengths, the tablets passed the European Pharmacopoeia test for uniformity of content of single-dose preparations. Only the 0.5 mg strengths passed the test of uniformity of dosage units. The excipient composition should still be optimized to improve the mechanical strength of the products. The overall preparation time of the formulations should be reduced, for example by shortening the drying time, to make semi-solid extrusion suitable for extemporaneus preparations in hospitals.

Tablets are solid medicinal products that are produced by compressing tablet mass in a tablet press. The reproducible and reliable functionality of the manufacturing process, facilities and equipment used in the manufacturing process of medicinal products must be validated. There must be a marketing authorisation for the sale of medicinal products, and pharmaceutical companies must comply with current legislation, Good Manufacturing Practices, and other binding guidelines. After marketing authorisation, certain changes, such as significant changes related to the manufacturing process or raw materials, must be notified to the competent authority by means of a variation application. Depending on the extent of the change, a revalidation and/or a regulatory approval before implementing the change may be required, which makes manufacturing process modification slow, expensive, and laborious. However, the pressure to enhance pharmaceutical manufacturing processes and reduce costs is prevailing. In this study, Lean Six Sigma methods were applied to enhance the manufacturing process of a tablet product. The study was divided into two parts. In the first part of the study, the objective was to investigate the manufacturing process of a tablet product X and to identify improvement actions that would make the manufacturing process of the tablet product X more efficient by achieving material and time savings. In addition, improvement actions were prioritized based on the benefits achieved by the improvement actions and the difficulty of implementation. The second part of the study was based on the improvement action selected from the first part of the study. The objective of the second part of the study was to investigate the factors influencing the amount of mass loss during tableting and how the amount of mass loss can be influenced. In this study, mass loss during tableting referred to the dusty mass inside the tablet press during tableting, which is removed from the tablet press to the equipment dedusting system. The purpose of the practical experiment conducted in the tablet production, which was part of the second part of the study, was to investigate how the magnitude of the exhaust airflow and fan power of the equipment dedusting system affects the amount of mass loss generated during tableting. Based on the experiment, adjusting the power of the equipment dedusting system can affect the amount of mass loss generated during tableting. However, further studies are needed to ensure that no dusty mass remains in the piping of the dedusting system or in tablet press at low exhaust airflow and fan power values during tableting. If the results are applied to other tablet products, the effect of a different formulation on powder dusting should be considered. Adequate dedusting during tableting is important so that the dusty mass inside the tablet press is removed as intended, facilitating the cleaning of the tablet press after tableting and reducing the risk of cross-contamination and exposure of workers to dust. The conclusion of this study is that Lean Six Sigma methods can be used more extensively to enhance the manufacturing processes of both tablet products and other pharmaceutical dosage forms and to reduce loss generated during the manufacturing process without revalidation or changes to a valid marketing authorisation.