Most of the targeted discoveries in tuberculosis research have covered previously explored chemical structures but neglected physiochemical properties. Until now, no efficient prediction tools have been developed to discriminate the novelty of screened compounds at early stages. To overcome this deficit, a drastic novel approach must include physicochemical properties filters provided by Chemical Global Positioning System-Natural Product analysis (ChemGPS-NP). Three different screening schemes GSK, GVKBio, and NIAID provided 776, 2880, and 3779 compounds respectively and were evaluated based on their physicochemical properties and thereby proposed as deduction examples. Charting the physiochemical property spaces of these sets identified the merits and demerits of each screening scheme by simply observing the distribution over the chemical property space. We found that GSK screening set was confined to a certain space, losing potentially active compounds when compared with an in-house constructed 459 highly active compounds (active set), while the GVKBio and NIAID screening schemes were evenly distributed through space. The latter two sets had the advantage, as they have covered a larger space and presented compounds with additional variety of properties and activities. The in-house active set was cross-validated with MycPermCheck and SmartsFilter to be able to identify priority compounds. The model demonstrated undiscovered spaces when matched with Maybridge drug-like space, providing further potential targets. These undiscovered spaces should be considered in any future investigations. We have included the most active compounds along with permeability and toxicity filters as supplemented material.

Bakgrund och syfte: Södersjukhusets avdelning för vård och omsorg (vo) Ortopedi har inte tidigare i någon större utsträckning undersökt följsamheten till PRISS-riktlinjer som används för att förhindra protesrelaterade infektioner (PJI). Syftet med arbetet var att undersöka följsamheten av PRISS-riktlinjer för antibiotikaprofylax (ABP) vid elektiv knäprotesoperation (KPO) på Södersjukhuset vo Ortopedi. Resultatet från arbetet kommer användas som grund för kvalitetshöjande åtgärder.

Metod: Journalgranskning utfördes av 273 elektiva KPO som opererats år 2016. Information kring ABP, operationstid, riskfaktorer och så vidare, extraherades ur journalerna och jämfördes sedan mot PRISS-riktlinjer. En annan metod användes för att jämföra icke-infekterade patienter från 2016 med infekterade patienter från år 2016 och år 2017 med hänseende på riskfaktorer. Två patienter som opererats under år 2016 och infekterats exkluderades från den icke infekterade populationen. Med en revisionsriskmodell jämfördes riskfaktorerna för 271 icke-infekterade patienter och fyra infekterade patienter.

Resultat: Profylax av kloxacillin och klindamycin gavs i adekvat tid till 48,2 % respektive 57,1 % av patienterna. De fyra PJI-fallen hade alla fått ABP-behandling som avvikit från PRISS- riktlinjerna. En patient erhöll fick ingen dos kloxacillin innan operation utan den gavs postoperativt. Medianen för revisionsrisken hos de två grupperna var 2,7 % för icke- infekterade och 2,5 % för infekterade patienter.

Slutsats: Följsamheten till PRISS- riktlinjerna var låg för både kloxacillin och klindamycin. Klindamycin gavs i stor utsträckning enligt samma doseringsschema som kloxacillin. Ortopediska avdelningens dokument ”ABP vid ortopediska ingrepp”, vilken används som förskrivarstöd för ABP är otydligt översatt från PRISS-riktlinjer. De fyra PJI patienterna fick ABP utanför PRISS- riktlinjer.

Paracetamol is crystallized in different solvents and techniques are developed and used to characterize the product. The product particles from three different solvent compositions: ethylene glycol, acetone and an acetone-water mixture (30-70 wt.%) have been examined. Product properties visually observed are quantified by image analysis and evaluation of measured image descriptors with Principal Component Analysis (PCA). The agglomerate strength has been determined by crushing single agglomerates. Depending on the solvent, the content of single crystals and agglomerates differ. Agglomerates differ by the number and size of crystals grown together, as well as by the strength.

Introduction: The β-lactam antibiotic aztreonam (ATM) interfere with the cell wall synthesis of Gram-negative bacteria to induce cell death. Bacteria become resistant by producing β-lactamases. Avibactam (AVI), a β-lactamase inhibitor, can protect ATM from degradation due to β-lactamases. An ongoing project at the INSERM Unit of Pharmacology of Antimicrobial Agents in Poitiers, France, aims to investigate the pharmacokinetic and pharmacodynamic (PKPD) features of ATM/AVI on 4 strains of enterobacteria using a semi-mechanistic PKPD model based on static time-kill studies. The intention is to validate the model with a hollow fiber infection model (HFIM). HFIM is a dynamic in vitro model mimicking the drug half-life that can be used to study different posologies to find a suitable dosing regimen. The first HFIM trials show a bacterial killing distinctly faster than predicted  and can not be used as validation.

Aim: To explain the faster bacterial killing in HFIM. Several theories are examined.

Methods: Comparing model simulations with static and dynamic HFIM experiments, to find an intrinsic feature of the HFIM system that could explain the differences in bacterial behaviour.

Results: It seems like a high flow from the central compartment to the cartridge could increase the bacterial killing. This could be due to a high input of nutrients, a high antibiotic exposure and by β-lactamases or bacterial signal substances being “washed” out of the cartridge.

Conclusion: When using HFIM as a validation method, it is important to be aware of factors that can affect the bacterial behaviour in the model. For bacterial strains producing β-lactamses this is particulary important. Eventhough, the HFIM could still be useful for simulating different posologies.

The aggregation propensity of peptide drug can affect its development, dosage forms, and route of administration. This behaviour can be influenced by other components in the system such as ions or charged molecules which interact with the amino acid residues. Therefore, understanding these interactions is important in developing a therapeutic peptide formulation. Molecular dynamic simulations can be an important computational tool in the understanding of peptide aggregation behaviours. It can provide conformational, structural, and chemical properties which are important to understand the aggregation kinetics and propensity of the peptides. In this study, All-Atom Molecular Dynamics (AA-MD) method were applied to investigate the detail of molecular-level interaction patterns between Degarelix and different counterions i.e. chloride, acetate and gluconate. Each simulation system were consisted of 20 peptide molecules representing 10 mM concentration. Simulations with two different peptide-counterion concentration ratios i.e. 1:1 and 1:2 were performed for acetate and gluconate, while for chloride, the simulation was performed only at 1:1 peptide-counterion ratio. At a specific peptide-counterion ratio, we did not observe significant differences in aggregation behaviour of Degarelix in terms of aggregations size distribution, percentage of free monomers or number of aggregates in the presence of different counterions. However, the detailed contact map between peptide amino acids and counterions as well as hbonds and radial distribution function analysis showed that gluconate and chloride interact the most and least with the Degarelix peptides respectively. The increase of counterion concentration (from 1:1 to 1:2 peptide-counterion ratio) for acetate and gluconate in the system showed an increased peptide-counterion interaction i.e. higher number of peptide-counterion hbonds and contacts as well as an increased aggregation tendency of Degarelix. Overall, the results from our study suggest that AA-MD simulations are capable of capturing the different interaction pattern between Degarelix and different counterions at the molecular-level. Also, the results showed that counterion concentration can impact the aggregation propensity of Degarelix.

Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.

The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.

Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.

The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.

The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization. 

Syre transporteras i kroppen från lungorna till vävnader bundet till hemoglobin i erytrocyter. Specifikt i hemoglobin är det järnatomen som binder syret. För att det ska bildas erytrocyter är det nödvändigt med järn, folsyra och vitamin B12. Brist på dessa leder till anemi. 

Anemi drabbar ca 1/3 av världens befolkning. Det definieras som minskning av friska erytrocyter och leder till att kroppens vävnader inte får tillräckligt med syre. Den vanligaste formen av anemi orsakas av järnbrist. Järnbrist förekommer i två former: absolut eller funktionell. Absolut järnbrist är centralt i detta arbete och innebär låga eller tomma järnförråd som kan leda till järnbristanemi. Denna sker vid bland annat ökat behov, minskat upptag av järn från födan, malabsorption eller kroniska blödningar. Ungefär 1,2 miljarder människor i världen idag har järnbristanemi. De vanligaste symtomen är huvudvärk, blek hud, trötthet och dyspné. Under graviditeten så tredubblas järnbehovet för att kunna försörja moderns ökande blodvolym och erytrocyter, tillväxten av fostret samt placentan och för att kompensera för blodförlusten vid förlossningen. Har man låga eller tomma järnförråd innan graviditeten så riskerar man järnbristanemi. Järnbristanemi hos gravida ökar risken för prematur födsel, låg födelsevikt och missfall. Risken för mödradödlighet har en direkt korrelation med järnbrisanemins svårighetsgrad. Om järnbristanemi lämnas obehandlad så har det nyfödda barnet en ökad risk att själv drabbas av järnbristanemi och det kan även ha en negativ påverkan på barnets kognitiva utveckling. Vid behandling av järnbristanemi ges i första hand oralt järn men vid svårare fall så ges intravenöst järn.

Syftet med studien var att jämföra effektivitet och säkerhet av intravenös och oral järn-administration vid järnbristanemi i samband med graviditet och postpartum hos kvinnor.

Metoden som används går ut på flera sökningar på Pubmed där sex kliniska studier som passar frågeställningen valdes ut för arbetet.

Resultatet från alla dessa artiklar pekar på att intravenös behandling av järnbristanemi är mer effektiv på att öka Hb värden och järndepåer med ökad följsamhet och mindre antal biverkningar. Av det testade preparaten gav järnkarboxymaltos mest lovande resultat.

Trots att arbetet hade flera begränsningar som kunde ha förbättrats genom att använda fler homogena kliniska studier så gynnade resultaten från alla sex studier den intravenösa behandlingen över den orala behandlingen. Dock borde alla gravida kvinnor ta oralt järntillskott tidigt i förebyggande syfte, redan under den första trimestern för att undvika utveckling av järnbristanemi. Intravenöst järn bör användas som sista utväg vid svårare typer av anemi, malabsorption samt för att öka följsamheten. 

Cancer är en av de vanligaste sjukdomarna i världen och den mest dominerade cancerformen är bröstcancer, vilket visades i en rapport från 2020 där 7,8 kvinnor hade fått bröstcancer under de senaste fem åren. Postoperativ strålbehandling, cytostatika och/eller hormonellbehandling är exempel på tilläggsbehandlingar som ofta ges vid bröstcancer. Dessa behandlingar ges i förbyggande syfte för att på så vis minska risken för sjukdomen att återkomma eller förvärras. Vid bröstcancer är det vanligt att det sker mutationer i PI3K-signalvägen, vid aktivering av denna signalväg orsakas ofta av mutationer i PI3K-subenheten p110α (PIK3CA). När PIK3CA muteras främjas tumörtillväxt, progression och resistens mot cancerbehandlingen. Apelisib är ett läkemedel som intas oralt och som verkar som en alfa-specifik PI3K-hämmare som selektivt hämmar isoformen PIK3CA. Genom att hämma den specifika isoformen PIK3CA förväntas risken för behandlingsrelaterad toxicitet minska och det terapeutiska fönstret förbättras, i jämförelse med en hämmare som är mindre selektiv. Syftet med detta fördjupningsprojekt var att undersöka hur apelisib påverkar utfallsmåtten: progressionsfri överlevnad, total överlevnad och total svarsfrekvens bland patienter med PIK3CA-muterad bröstcancer. Studiedesignen som tillämpades var en systematisk litteraturstudie baserad på åtta olika originalartiklar som hittades via databasen PubMed. Resultatet visade hur väl apelisib behandlingen fungerade hos patienter med PIK3CA-muterad bröstcancer som har haft sin sjukdomsprognos förvärrad.

Introduktion: Huden är människans största organ och dess funktion är att skydda kroppen mot uttorkning och främmande ämnen. Huden kan delas upp i flera lager: underhuden, läderhuden och överhuden. Överhuden utgörs av stratum corneum som huvudsakligen ansvarar för hudbarriärens egenskaper och som begränsar dess penetration.  

Syfte: Syftet med studien är att studera vilken typ av formulering som kan förbättra penetrationen av vattenlösliga och svårpenetrerande ämnen som hyaluronsyra och azelainsyra genom hudbarriären. 

Metod: En systematisk litteraturöversikt har gjorts genom att söka efter originalartiklar via databasen Web of Science med hjälp av inklusions- och exklusionskriterier. 

Resultat: Penetrationstester av olika nanoformuleringar av hyaluronsyra och azelainsyra utfördes. Variationer i molekylvikt och partikelstorlek av hyaluronsyra, liksom mängden ytaktiva, ämnen gav olika penetreringsdjup i huden. 

Diskussion: För att förbättra penetrationen av hyaluronsyra och azelainsyra genom stratum corneum bör aspekter såsom molekylvikt, partikel/droppstorlek, viskositet, koncentration liksom val av vehikel tas hänsyn till vid formulering. 

Slutsats: Nanoemulsioner visade sig vara en optimal formulering för att förbättra penetrationen av hyaluronsyra och azelainsyra, tack vare minskning av partikelstorlek samt de lipofila egenskaperna i gemenskap med hudbarriären.

Abstrakt

Introduktion

Vid astma är luftrören kroniskt inflammerade och immunförsvarets celler är involverade. En sådan typ av celler är eosinofiler och en typ av astma är eosinofil astma. Eosinofiler aktiveras av interleukin-5 (IL-5) och därmed är IL-5 och dess receptor lämpliga mål för behandling. År 2018 fanns tre läkemedel med tre olika monoklonala antikroppar, mepolizumab, reslizumab och benralizumab, där det första av läkemedlen blev godkänt 2015. Forskningsläget utifrån studier publicerade efter mars 2017 var ej sammanställt.

Syfte

Att via systematiska litteratursökningar undersöka om tillägg av anti-IL-5-behandling till standardbehandling vid astma kunde minska antalet exacerbationer, förbättra lungfunktionen och förbättra livskvalitén hos vuxna och barn över 12 år med måttlig till svår eosinofil astma, samt att utvärdera hur vanliga biverkningar var i samband med behandlingen.

Material och metoder

Systematiska litteratursökningar genomfördes i databasen PubMed och begränsningar gjordes till artiklar publicerade efter 1 mars 2017. Urval gjordes i tre steg efter titel, abstrakt och artikel i fulltext. Relevans bedömdes utifrån mallar från SBU och de artiklar som ansågs vara relevanta kvalitetsgranskades sedan efter mallar från SBU.

Resultat

Fem artiklar inkluderades, tre stycken hade undersökt benralizumab och de resterande två mepolizumab respektive reslizumab. I studien om mepolizumab minskades antalet exacerbationer med statistisk signifikans. I studien om reslizumab kunde statistiska signifikanta förbättringar identifieras med avseende på FEV1 och livskvalité. För benralizumab kunde förbättringar av FEV1, livskvalité och minskningar av antalet exacerbationer identifieras. Studien om mepolizumab var liten och det var oklart om uppföljningen av biverkningar var systematisk. I studien om reslizumab upplevde 9 % av patienterna incidenter som kunde relateras till behandlingen. I studierna om benralizumab var allvarliga incidenter relativt ovanliga. De flesta vanliga biverkningarna var representerade i alla tre studierna och bland dem var de vanligaste nasofaryngit och förvärrad astma.

Slutsats

Tendenser fanns till att anti-IL-5-behandling kunde minska antalet exacerbationer, förbättra lungfunktionen och livskvalitén hos vuxna och barn över 12 år med måttlig till svår eosinofil astma och samtidig standardbehandling. Behandlingen föreföll endast i liten grad ge allvarliga biverkningar, men fler och mer långsiktiga studier behövs inom det området.

Introduktion: Den ständigt växande befolkningen med ökad andel äldre medför en högre läkemedelsbörda och en mer komplex medicinsk behandling. Ett föreslaget sätt att hantera den ökande läkemedelskomplexiteten är att inkorporera kliniskt arbetande apotekare i vårdkedjan för utförande av läkemedelsgenomgångar (LMG). Syfte: Huvudsyftet var att utvärdera resultatet av en klinisk apotekares LMG inom primärvården i Bålsta. Utvärderingen gjordes som en del i det pågående arbetet kring att undersöka om implementering av kliniskt arbetande apotekare inom den svenska primärvården kan förbättra patienters läkemedelsanvändning. Metoder: Utvärdering av 110 patienters läkemedelsgenomgångar utförda av apotekare vid två olika vårdcentraler gjordes med hjälp av kvalitetsverktyget ”Medication Appropriateness Index” (MAI). Även Socialstyrelsens publikation ”Indikatorer för god läkemedelsterapi hos äldre” samt interaktionsdatabasen Janusmed användes. Patientunderlag återfanns i det elektroniska journalsystemet Cosmic samt i fysiska dosrecept. Resultat: Förändring från 10,1 (± 8,9) poäng till 4,1 (± 4,7) poäng enligt MAI uppvisades i snitt efter genomförd LMG. Detta innebar en statistiskt signifikant minskning och därmed en ökad behandlingslämplighet. Antal olämpliga läkemedel var 23 före genomgång och 14 efter. Av apotekare framlagda förslag genererade en total genomförandefrekvens á 51%, där muntlig kommunikation medförde högst andel genomförda förslag. Sammanfattning: Utvärderingen visade en förbättring av läkemedelsbehandlingars lämplighet med avseende på MAI och antal förskrivna olämpliga läkemedel. Muntlig kommunikation genererade störst andel genomförda förslag och gynnade samarbetet mellan berörda professioner. Sammantaget verkar implementering av apotekarledda LMG i pirmärvården ha potential att bidra till en förbättrad läkemedelsanvändning.

Clozapine has superior efficacy to other antipsychotics yet is underutilized due to its adverse effects, such as neutropenia, weight gain, and tachycardia. The current investigation aimed to introduce a pharmacometric approach to simultaneously model drug adverse effects, with examples from schizophrenia spectrum patients receiving clozapine. The adverse drug effects were represented as a function of time by incorporating a mixture model to describe individual susceptibility to the adverse effects. Applications of the proposed method were presented by analyzing retrospective data from patients’ medical records in Psychiatric Clinic, Penang General Hospital. Tachycardia, weight gain, and absolute neutrophils count (ANC) decrease were best described by an offset, a piecewise linear, and a transient surge function, respectively. 42.9% of the patients had all the adverse effects, including weight gain (0.01 kg/m² increase every week over a baseline of 24.7 kg/m² until stabilizing at 279 weeks), ANC decrease (20% decrease from 4540 cells/µL week 12-20.8), and tachycardia (14% constant increase over a baseline of 87.9 bpm for a clozapine maintenance dose of 450 mg daily). 32.5% of the patients had only tachycardia, while the remaining 24.6% had none of the adverse effects. A new pharmacometric approach was proposed to describe adverse drug effects with examples of clozapine-induced weight gain, ANC drop, and tachycardia. The current approach described the longitudinal time changes of continuous data while assessing patient susceptibility. Furthermore, the model revealed the possible co-existence of ANC drop and weight gain; thus, neutrophil monitoring might predict future changes in body weight.

This study focused on the investigation of the permeation enhancing effects of a stomach targeted, nanoparticulate drug delivery system. The polyacrylic acid–cysteine/polyvinylpyrrolidon nanoparticles were loaded with the magnetic resonance imaging (MRI) contrast agent diethylenetriaminepentaacetic acid gadolinium( III)dihydrogen salt (Gd-DTPA). Average particle size was determined to be 130nm and the optimum for stability was found to be below a pH of 4.5. In vitro permeation studies were performed on rat gastric mucosa and revealed an eightfold increase in Gd- DTPA uptake when incorporated in the nanoparticles compared to evaluation in the presence of unformulated polyacrylic acid–cysteine. In vivo investigations with rats were performed via the noninvasive MRI method in order to track the nanoparticles way through the gastrointestinal tract. When Gd-DTPA was administered orally as nanoparticulate suspension, an increased MRI signal in the urinary bladder was detected after 34 min, providing evidence for systemic uptake and renal elimination of the contrast agent. As control experiments with Gd-DTPA only or in combination with unformulated polyacrylic acid–cysteine revealed no MRI signal increase at all, the significant permeation enhancing effect could be identified based on the nanoparticulate formulation.

Introduction: The plant derived cyclotide MCoTI-I’s (Momordica cochinchinensis trypsin inhibitor I) distribution in the central nervous system (CNS) was estimated in the project. Cyclotides were cyclic peptides characterized by a stabile chemical structure with extraordinary resistance against physiological degradation. This provided hope in development of MCoTI-I as a scaffold for drugs across the blood brain barrier (BBB).

Aim: The project aimed for development of a bioanalytical method for MCoTI-I to use in vitro methods for characterization of pharmacokinetic parameters related to the distribution in the CNS, intended for future pharmaceutical development of MCoTI-I.

Materials and Methods: Liquid Chromatography coupled to Mass Spectrometric system was used for bioanalysis. Equilibrium dialysis and the Brain Slice method was applied to obtain the fraction unbound (f_u) in plasma and brain tissue, unbound distribution volume (V_u,brain) in the CNS and the unbound intra-to-extracellular concentration ratio (K_p,uu,cell). K_p,uu,brain  (unbound blood to brain concentration ratio at steady state) was calculated through data of MCoTI-I from a parallel ongoing project.

Results: An analytical method was successfully developed with linearity R²-values of 0.999 in plasma and 0.988 in brain homogenate. F_u,plasma, f_u,brain, V_u,brain, K_p,uu,cell and K_p,uu,brain  was quantified through the methods and equations.

Conclusions:  MCoTI-I had a high binding to tissue and cellular uptake in the brain parenchyma. However, the cyclotide did not cross the BBB. The pharmacokinetic information could serve for future research on MCoTI-I in other organs and tissues. 

BACKGROUND: Some cases of autism spectrum disorder (ASD) are associated with genetic causes. A micro deletion on the human chromosome 16p11.2 is the most common. A mouse model with this deletion demonstrates functional abnormalities in the basal ganglia (BG), mainly the striatum. 5-HT_2A receptors are also present in the striatum and may provide substrate for modulating the BG circuitry that possibly has a crucial role in ASD. AIM: To examine neuron activity in the striatum, qualitatively observe the distribution of the 5-HT_2A receptor in the striatum and pharmacologically investigate serotonin 5-HT_2A involvement in the behavioral abnormalities found in 16p11.2 deletion mice. METHODS: Expression of the gene product of c-fos was measured using immunohistochemistry to provide a measure of neural activity. Autoradiography was used to describe the distribution of the 5-HT_2A receptors in the striatum. The effect of risperidone and M100907 on 16p11.2 deletion mice was assayed using the forced swim test. RESULTS: A significant increase in c-fos expression in the dorsal striatum in mutant mice was observed. Both normal and deletion mice exhibited receptor binding to 5-HT_2A in the striatum. A significant decrease in mobility in the forced swim test in both mutant and wild type mice was observed only when risperidone was administrated compared to controls and M100907. CONCLUSION: Elevated c-fos expression in the dorsal striatum indicates altered activity in dorsal striatum in this ASD mouse model. 5-HT_2A receptor binding in the striatum is qualitatively similar in both genotypes. Risperidone had a greater effect than M100907 in normalizing behavioral response in the swim, yet further dose-response and behavioral studies has to be done for more accurate determinations about the involvement of 5-HT_2A as a possible pharmacological target for treatment in autism.

Bipolär sjukdom tyder på en långvarig sjukdom och identifieras av periodiska maniereller hypermanier och depression. Sjukdomen ger upphov till försämring av välmående,och med underskridande episoder av mani och depression. Syftet med föreliggandestudie har varit att undersöka om det nya läkemedlet kariprazin kan minska symptomenvid bipolär sjukdom. Under studiens gång har en systematisk litteraturöversiktgenomförts för att granska resultat och biverkningsprofil vid behandling medläkemedlet kariprazin. Litteraturöversikten har genomförts genom att jämföra studiersom undersöker kariprazin kontra placebo som behandling mot bipolär sjukdom. Vidartikelsökningen användes databasen PubMed. Resultatet av föreliggande studie visaratt det är större signifikans att fler kariprazinbehandlade patienter uppfyller remissionoch kriterierna för YMRS-svar än placebo patienter och att kariprazin har en signifikanteffekt på förbättring av symtom associerade med bipolär sjukdom typ 1. Uppkomsten avde vanligaste biverkningarna vid behandling med kariprazin var extrapyramidalstörning, huvudvärk, akatisi och illamående. Slutsatsen i föreliggande studie visardärmed att kariprazin som helhet kan ha en god tolerabilitet och därmed anses vara ettbehandlingsalternativ för symtom vid bipolär sjukdom typ 1. Uppkommandebiverkningar från behandlingen klassificeras sedermera i mild eller måttligsvårighetsgrad.Nyckelord: Bipolär sjukdom, kariprazin, litteraturstudie, effekt, säkerhet.

Bakground:

The unbound drug volume of distribution in the brain (V_u,brain) is a parameter describing the overall binding and distribution of a drug inside the brain parenchyma and relates it to the physiological volumes in the brain, taking into account specific and non-specific binding as well as active transport and pH partitioning of the compound.

Aim:

To build and validate an in silico projection to latent structures (PLS) model to predict V_u,brain from computed physicochemical properties of drugs.

Materials and Methods:

The dataset consisted of a combination of Fridén et al. (2009) and Loryan et al. (2015) datasets containing 81 CNS and non-CNS drugs with 158 computed molecular descriptors, which was utilized to develop a PLS model using SIMCA 15 and MODDE 11 (Umetrics, Sweden). The model building workflow comprised of 8 steps, where in step (1) the dataset was pre-processed, (2) the PLS model was created followed by the assessment of the determination coefficient (R²), cross-validated determination coefficient (Q²) and (3) overviewing plots. Thereby the evaluation of (4) regression coefficients and (5) variable importance for projection (VIP) along with (6) correlation matrix to remove insignificant variables. Steps 2-6 are iterative and are involved in model optimization. The final model was then (7) internally and (8) externally validated.

Results:

Vu,brain was log-transformed (mean=1.26). The final PLS model (R²Y(cumulative)=0.81 and Q²(cumulative)=0.75) developed on the training set (n=53), consisted of 3 PLS components and was based on 12 molecular descriptors, of which CLogP, Jurs_RASA and TPSA were most important. The external validation using test set (n=28) resulted in the root mean square error of prediction (RMSEP) of 0.37, where 23/28 drugs were within 2-fold variation.

Discussion:

The PLS model is still under development and needs independent dataset as external validation to become finalized.

Introduktion: Framställning av hydrogeler som efterliknar tumörers extracellulär matris är eftertraktad för att studera läkemedelsdiffusion. Diffusionskoefficienterna av doxorubicin och idarubicin i AG bestämdes med hjälp av UV-imaging. Denna metod används för att studera koncentrationsprofiler, genom att mäta absorbansen över tid och avstånd. Syfte: Att undersöka stabiliteten hos AG, doxorubicin och idarubicin samt att kvantifiera diffusionen av doxorubicin och idarubicin genom AG med UV-imaging. Metod: Massförlusten för en AG som förvarades vid olika temperaturer studerades. Det utfördes en våglängdsscreening för substanserna med plattläsare samt undersökningar av UV-stabilitet och temperaturstabilitet i tre timmar med UV-imaging. Diffusionskoefficienten bestämdes för en substanslösning som var i direktkontakt med en AG i en diffusionscell. Resultat: Geler med 1 viktsprocent agaros har större temperaturstabilitet än geler med 2 viktsprocent.  Absorbansmätningarna från undersökningen av UV- och temperaturstabilitet tyder på att substanserna bryts ner av UV- och/eller temperaturändringar. Diffusionskoefficienterna är högre för 500 µM lösning med pH 6,4 jämfört med 1000 µM lösning respektive pH 7,4. Diffusionskoefficienterna för 500 µM doxorubicin är högre än idarubicin och omvänt vid 1000 µM lösning. Diskussion: Både doxorubicin och idarubicin är känsliga för nerbrytning vid kroppenstemperatur (37°C) och UV-strålningar. Diffusionskoefficienterna kunde därför kvantifieras med UV-imaging. Både molekylens egenskaper och lösligheten för substansen, som påverkas av bland annat pH-värdet för mediet, är begränsande faktorer för diffusionen.

Background: It is incredibly important to ensure proper medication adherence as well as inhalation technique to control asthma and (COPD) chronic obstructive pulmonary disease. Both are required to achieve a full treatment effectiveness. Providing services in these two areas is the role of community pharmacists.

Aim: This study aims to determine whether pharmacy interventions can result in improved inhalation technique and adherence to medication in asthma and COPD patients in relation to reduced hospitalizations and severe exacerbations.

Methods: A systematic literature search was performed in the database PubMed and was carried out in the fall of 2022. SBU gallery was used for relevance assessment and followed as a method (Appendix 1). Inclusion criteria for the studies were determined according to PICO.

Results: This review examined seven studies showing the positive improving impact of community pharmacists' on patients' adherence to inhaled medicine and inhalation technique for asthma and COPD patients. Some studies have demonstrated that this method of treatment can reduce hospitalizations and severe exacerbations, but few studies have been conducted in this area. In addition, research is needed to determine the ideal frequency for educating and rechecking inhaler techniques in order to prevent technique degradation in patients.

Conclusions: In this review, it was shown that community pharmacists can play an important role in managing asthma and COPD, particularly in educating patients about inhaler technique and making sure that their medication is taken as prescribed. Despite this, their role in this area is yet to be fully appreciated, requiring more research.

Many patients with psychotic symptoms respond poorly to treatment. Various approaches have been made to classify these patients according to treatment response. However, existing classifications have been criticized for various reasons and a new classification system is needed. Further, no satisfactory explanation of the poor treatment response has been apparent. The general aim of this thesis was therefore to develop and validate a new classification method of functional remission in a naturalistic population of patients with psychosis and to utilize this classification to investigate the population from genetic, drug treatment, insight and social network points of view.

Data for this cross-sectional study of patients (n=123) attending the Psychosis Outpatient Care clinic in the county of Jönköping, Sweden, were obtained from patient interviews, blood samples and information from patient files. The new classification method CANSEPT, which combines the CAN rating scale (CAN), the UKU side effect rating scale (SE) and the patient’s previous treatment history (PT), showed validity in discriminating the patients and was accepted well by the patients. CANSEPT was used to group the patients in the other studies in this thesis.

The results indicated that the gene polymorphism ABCB1 3435T, was related to worse significant social and clinical needs for patients on olanzapine, while the polymorphism DRD2 Taq1 A1 was related to a greater risk of significant side effects; especially if male, or taking strong dopamine D2-receptor antagonistic drugs. Drug treatment factors were also related to treatment response; longer duration of untreated prodromal and early psychosis was seen for patients with current significant social and clinical needs and non-adherence to treatment was associated with worse significant side effects. Worse treatment outcomes also appeared to be associated with smaller social network groups, worse insight into illness, poorer knowledge of warning signs and worse coping strategies.

In summary, CANSEPT was shown to be a useful valid, multidimensional tool for classification of treatment response. Gene polymorphisms, duration of untreated illness, non-adherence to treatment, social networks and knowledge should be taken into consideration when investigating inadequate treatment response.

RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

I Sverige är abort en laglig rättighet och det finns flera godkända metoder för regelbunden antikonception. Ändå finns ett behov av akutmetoder för att förhindra oönskad graviditet.  Det finns tre godkända akutpreventivmedelsmetoder; levonorgestrel, ulipristal och kopparspiral. Detta arbetes syfte var att undersöka effektivitet och säkerhet för dessa tre godkända metoder. En litteratursökning gjordes i databasen PubMed,  7 artiklar valdes ut för analys. Artikel 1och 2 undersökte levonorgestrels effektivitet och säkerhet och kunde redovisa graviditetsfrekvenser på 0, 57%  och 0,67 % , samt en graviditetsförebyggande effektivitet på 68 %. Artikel 3 jämförde ulipristal och levonorgestrel och redovisade graviditetsfrekvenser på 1,8 % för ulipristal och 2,6 % för levonorgestrel. Även ”non-inferiority” konstaterades med OR på 0,68. Artikel 4 undersökte levonorgestrels effektivitet och redovisade graviditetsfrekvenser på 2,0 % (12 h- gruppen) och 1,9 % (24 h- gruppen), dessutom redovisades en graviditetsförebyggande effektivitet på 72 % (12 h- gruppen) och 75 % (24 h- gruppen). Artikel 5 jämförde ulipristal och levonorgestrel och fann att ulipristalbehandling  är ”non-inferiority” till levonorgestrelbehandling. Artikel 6 undersökte ulipristals effektivitet och redovisade en graviditetsfrekvens på 2, 1 % och en graviditetsförebyggande effektivitet på  62, 3%. Artikel 7 undersökte kopparspiralens effektivitet och kunde redovisa 100 % graviditetsförebyggande effektivitet. Akutpreventivmedel fungerar inte alltid, men förhindrar oönskade graviditeter. Slutsatsen är att resultaten ger stöd för gällande behandlingsrekommendationer.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.

There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field.

Sex Differences in the Use of Pain Medication in Sweden and Denmark

Abstract

Background: Pain is a multifaceted experience and understanding its mechanisms and effective treatment methods being of paramount interest. Sex differences in pain perception, treatment, and response are increasingly recognized as pivotal areas of investigation.

Aim: This study aims to compare the usage patterns of analgesic medications between Sweden and Denmark, focusing on sex and gender differences.

Method: A quantitative cross-sectional study utilizing aggregated individual-level data from national registries in Sweden and Denmark was conducted. The study focused on prescribed analgesic medications, including NSAIDs (M01A), paracetamol including combinations (N02BE), salicylic acid and derivatives (N02BA), and opioids (N02A), identified by their respective ATC- code. The analysis encompassed adult individuals aged 25 and above, in total and divided into three age groups. The studied measure was period prevalence, defined as the number of individuals per 1000 inhabitants that purchased at least one prescription during the year. Differences between men and women were calculated as risk ratios (RRs). Data were collected for the years 2022 and 2010 to provide a comparative analysis over time.

Results: Clear disparities in analgesic medication usage between men and women were observed in both countries in 2022, with women generally exhibiting higher utilization rates compared to men. In Sweden, risk ratios (men/women) for NSAIDs, opioids, salicylic acid derivatives, and paracetamol including combinations were 0.76, 0.75, 0.50, and 0.63, respectively. In Denmark, similar trends were observed. The risk ratios for NSAIDs, opioids, salicylic acid derivatives, and paracetamol including combinations were 0.83, 0.78, 0.76, and 0.70, respectively. Analysis of trends from 2010 to 2022 showed change in sex differences in drug use. Furthermore, variations in usage patterns were noted between age groups.

Conclusion: This study underscores the presence of sex disparities in analgesic medication usage in Sweden and Denmark in 2022. These disparities persist across different age groups and between the two countries.

In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).

Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.

Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.

Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.

Background: The increased use of medicines in recent decades has affected the environmentand led to negative consequences. Environmental risk for a drug can be classified by using PBTindex and PEC / PNEC-ratio. Environmental risk information can be found on the knowledgesupport websites "medicines and the environment" at Janusinfo.se and in environmentalinformation at Fass.se. The Drug- and Therapeutics Committees (DTCs) ensure that medicinesare used in a correct and cost-effective manner and recommend medicines in annually updatedguidelines.

Method: A survey was created and pilot-tested by 10 persons experienced from DTCs. Thequestionnaire consisted of four parts, general questions, questions about the use of theknowledge support "medicines and the environment" on janusinfo, questions about the use ofenvironmental information from Fass.se and other questions about environmental aspects.

Result: In total, 9 out of 10 people who were included in the pilot study answered. Threerespondents had only positive feedback on the questionnaires. Some respondents thought thatthere were some questions and answers’ options that were not easy to understand and that somequestions could be answered only by people familiar with the subject.Conclusions:

The conclusion is that the pilot study has led to many improvements in surveyquestions and approaches. In the future, further research is needed for knowledge about drugeffects in the environment. 

Formulations for buccal drug delivery often comprise polymers to facilitate mucoadhesion based on water sorption. The main objective of the current study was therefore to evaluate the effect of dehydration on drug uptake through oral mucosa. We have used diffusion cells with excised porcine mucosa to study uptake of three alternative drugs (i.e., Metronidazole, Benzydamine and Xylometazoline) together with polyethylene glycol (PEG) as the model polymer for adjusting water activity in the test solutions. Taking drug activity into account, we can conclude that addition of PEG results in a drug flux through mucosa that is about two times lower for Metronidazole and more than 40 times lower for Xylometazoline compared to that from a pure PBS-solution. However, for Benzydamine the uptake through mucosa was more or less the same, which could possibly be due to the high PEG-concentration (65 wt%) affecting the dissociation constant and thus the permeability. These results indicate that an increased water gradient may have the same limiting effect on permeability through oral mucosa as previously seen for skin. Thus, water gradient effects should be a factor to consider when developing buccal adhesive formulations.

Formulations for nasal drug delivery often rely on water sorption to adhere to the mucosa, which also causes a higher water gradient over the tissue and subsequent dehydration. The primary aim of this study was therefore to evaluate mucosal response to dehydration and resolve the hypothesis that mucoadhesion achieved through water sorption could also be a constraint for drug absorption via the nasal route. The effect of altering water activity of the vehicle on Xylometazoline HCl and Cr-EDTA uptake was studied separately using flow through diffusion cells and excised porcine mucosa. We have shown that a modest increase in the water gradient over mucosa induces a substantial decrease in drug uptake for both Xylometazoline HCl and Cr-EDTA. A similar result was obtained when comparing two different vehicles on the market; Nasoferm (Nordic Drugs, Sweden) and BLOX4 (Bioglan, Sweden). Mucoadhesion based on water sorption can slow down drug uptake in the nasal cavity. However, a clinical study is required to determine whether prolonged duration of the vehicle or preventing dehydration of the mucosa is the most important factor for improving bioavailability.

Bakgrund: Lipidsänkande läkemedel, huvudsakligen statiner köptes under 2011 ut av 815 000 personer på landets apotek. Höga blodfetter är en viktig riskfaktor, bland flera, för utveckling av hjärt- och kärlsjukdom (ex hjärtinfarkt, kärlkramp, claudicatio intermittens och stroke). Hjärt- och kärlsjukdom orsakar drygt 40 % av alla dödsfall i Sverige. Livsstilsförändringar tillsammans med blodfettssänkande läkemedel, statiner, är en effektiv behandling. Statiner kan ges antingen i förebyggande syfte (primärprevention) eller som terapi vid sekundärprevention efter en första hjärt-kärlsjukdomshändelse.

Syfte: att med hjälp av publicerade kliniska prövningar och metaanalyser undersöka vilka primär- och sekundärpreventiv effekter statiner har på morbiditet/mortalitet vid hjärt- och kärlsjukdomar.

Resultat: utvärdering av utvalda artiklar, som redovisas i denna studie, visade att statiner minskar TC, LDL och TG och ökar HDL. De visade också en reducering av allvarliga hjärthändelser, cerebrovaskulära händelser, dödlighet i kranskärlssjukdom, instabil angina och revaskularisering. Statinbehandling var associerad med riskökning av måttlig eller allvarlig leversvikt, akut njursvikt, måttlig eller allvarlig myopati och grå starr både hos män och kvinnor. Risken var dosberoende och störst under första årets behandling.

Slutsats: studierna visade att statinbehandling minskar skadliga blodfetter, förhindrar aterosklerosprocessen och minskar därmed behovet av revaskularisering. Statinbehandlingen är cirka tre gånger så effektiv vid sekundärprevention som vid primärprevention. Man behöver behandla 60 personer, som haft en hjärt- och kärlhändelse, under cirka 5 år för att förhindra ett dödsfall och 180 personer för att förhindra ytterligare ett insjuknandetillfälle. Effekten är likartad för män och kvinnor och för äldre och medelålders personer. Livslängden ökar med två år. För patienter, som inte haft en hjärt- och kärlhändelse men har riskfaktor t.ex. i form av höga kolesterolvärden eller diabetes, behöver man behandla nästan 2-3 gånger så många för att uppnå samma resultat (120 patienter för att förhindra ett dödsfall och 330 för att förhindra ett insjuknande). Effekten vid primärprevention av friska individer är låg. Statiner är ur biverkningssynpunkt väletablerade och säkra läkemedel. Ett observandum är myopati, (rhablomyelos), som är ganska ovanligt enligt vad som inrapporterats från studier. Ett problem som finns med all preventiv behandling är dålig följsamhet till ordinationerna.

Our objectives were to document and compare plasma levels of Catecholamines, Cortisol,Glutathione and Malondialdehyde in camels after long term dehydration (20 days) in the presenceor absence of angiotensin II AT1 receptor blocker (Losartan) versus levels in non-dehydratedcamels; and to record the effects on glutathione and malondialdehyde activity in liver and kidneyhomogenate in the one-humped camel. Eighteen male camels were used in this study, sixcontrols, six dehydrated and treated with losartan (5mg/kg daily) and six were dehydrated withouttreatment. Our results revealed significant decrease (P<0.05) in plasma epinephrine level in bothtreated and dehydrated camels; while, Plasma norepinephrine showed significant increase in bothdehydrated groups (P< 0.01). Levels of plasma dopamine were also significantly increased (P<0.01) in both dehydrated groups compared to control camels.Plasma levels of cortisol increased significantly across dehydration with or without losartanadministration (P<0.01) compared with time-matched levels in control camels. Losartan had nosignificant modulating effect on the cortisol response to dehydration.Plasma, liver and kidney homogenates revealed significant increase (P<0.05) in glutathione levelsin both dehydrated groups compared to control.Plasma, liver and kidney homogenates for malondialdehyde levels in both treated and dehydratedcamels also showed significant increase (P<0.05 & P<0.01) compared to controls.In conclusion, our study demonstrates that the effect of dehydration with or without losartaninduced oxidative stress in these camels, leading to significant changes in plasma catecholaminesand cortisol levels, together with significant increments in glutathione and malondialdehydeactivities in plasma, liver and kidney homogenate to counter act the damaging effect of the freeradicals in the dehydrated camels.

Emerging resistance to antimicrobials is a global crisis driven by the overuse of antibiotics and diagnostic uncertainty, therefore reliable assays for rapid identification of bacteria and antimicrobial susceptibility testing are important. 

In this study, five antimicrobial peptides (AMPs) received from the Pharmacognosy research group were tested in rapid antimicrobial susceptibility testing, ASTar®. The aim was to study the stability of these peptides and develop a formulation intended for AST Disc to be used in ASTar. The stability of the peptides were investigated using high- performance liquid chromatography at different temperatures over time. Antibacterial assays with various approaches were performed to evaluate the antibacterial activity and use as a reference for ASTar. This was followed by AST Disc manufacturing loaded with AMPs in various concentrations. 

Antimicrobial susceptibility testing by ASTar resulted in a minimum inhibitory concentration (MIC) of 40 μM of LRS-21 against E. coli using the algorithm. However, the algorithm was not applicable to all AMPs and once the normalization formula was applied it resulted in MIC of 20 μM of LL-37 against E. coli and 80 μM against S. aureus. No antibacterial activity was exhibited in ASTar for the three remaining peptides (MIC>160 μM) against E. coli and S. aureus. 

These findings show that antimicrobial peptides can be tested using ASTar however the current algorithm is not applicable to all AMPs. The results of the thesis could be used for time-effective research of other AMPs, to understand their effectiveness against different bacterial strains, as they are of pharmaceutical interest, especially since the emergence of antibiotic resistance. 

α-synuclein is a 140 amino acid protein, abundant in the brain and its physiological concentration regulates neurotransmitter release. The disturbance in balance between generation and clearance of α-synuclein lead to aggregation of α-synuclein monomers into oligomers which play a key role in pathogenesis and progression of Parkinson’s disease (PD). PD is the second most common neurodegenerative disease and is estimated to affect 2% of the population at the age of 60 and above.  Immunotherapy is one of the promising approaches to treat PD and various monoclonal antibodies have been developed to target α-synuclein oligomers. SynO2, an IgG antibody is one such antibody which showed high binding affinity towards α-synuclein oligomers and fibrils. To treat the disease in early phase small α-synuclein oligomer is a potential target to prevent them from further aggregation. But bivalent IgG antibodies, because of a large spatial distance between their two arms, are unable to bind to small α-synuclein oligomers with avidity. To enhance the avidity and binding potential of the bivalent antibody SynO2, multivalent antibodies were designed where two and four single chain fragment variables (scFv) were fused on the binding site of the antibody to produce TetraSynO2 and HexaSynO2, respectively. Purpose of this study was to characterize the binding kinetics of TetraSynO2 and HexaSynO2 to α-synuclein oligomers. Recombinant Antibodies were produced using Expi293 system and were purified via affinity purification using Protein G column. Size of purified SynO2, TetraSynO2 and HexaSynO2 were 150 kDa, 201 kDa and 250 kDa, respectively and were stable when analysed via thermal stability assay. α-synuclein oligomers for usage in various binding assays were prepared and characterized. Different ELISA setups and real time interaction studies using LigandTracer were applied to study the avidity of SynO2 and binding kinetics of TetraSynO2 and HexaSynO2. The results showed that SynO2 binds much stronger than SynO2 Fab indicating that SynO2 binds with avidity. Cross reactivity with other amyloid proteins showed that SynO2 and HexaSynO2 had mild cross reactivity to amyloid beta. Furthermore, binding kinetics revealed that HexaSynO2 had increased binding strength with avidity to α-synuclein oligomers than SynO2 and TetraSynO2, which was attributed to the lower dissociation rate of HexaSynO2. In conclusion, multivalent antibodies showed stronger binding potential with avidity to α-synuclein oligomers compared to the bivalent antibody and provides a promising design for future intervention in diagnosis and treatment of PD. 

Neuropsychiatry is a medical field including a range of disorders that are associated with an impairment of the serotonergic and dopaminergic pathways, amongst others schizophrenia, bipolar- and major depressive disorder. Serotonin synthesis depends on cerebral availability of its amino acid precursor tryptophan, which is transported through the blood-brain barrier by isoforms of system-L and system-A. Variability of tryptophan transport is proposed as a cause for the monoamine synthesis alteration. Furthermore, a reduced amino acid uptake into different cerebral regions in presence of proinflammatory cytokines is among the suggested mechanisms causing major depressive disorder.   

Lithium and clozapine are used in the treatment of schizophrenia and bipolar disorder. Clozapine is an atypical antipsychotic drug, often clinically combined with the mood stabilizer lithium, whose mechanism of action is incompletely elucidated. The aim of the study was to examine the effect of lithium and clozapine, separately and in combination- on tryptophan uptake into fibroblast cell-lines from healthy volunteers, in presence of proinflammatory cytokines, specifically IL-1β.

Fibroblast cell-lines from healthy volunteers were utilized as an experimental model for the blood-brain barrier. The cells were treated with IL-Iβ, IL-1Ra (IL-Iβ antagonist), lithium, and clozapine in various constellations. Uptake of ¹⁴C-L-tryptophan across fibroblast cellular membranes was measured using the cluster tray method. Obtained results demonstrate an anti-inflammatory effect caused by lithium administration in fibroblast cell-lines from healthy individuals. Further investigations are required to draw a definitive conclusion about lithium's anti-inflammatory effect in healthy cell lines, and in patient cell lines.