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The smorgasbord of methods that we use within the field of pharmacometrics has developed steadily over several decades and is now a well-laid-out buffet. This thesis adds some garnish to the table in the form of small improvements to the handling of certain problems. The first problem tackled by the thesis was the challenge of saddle points and local non-identifiability when estimating pharmacometric model parameters. Substituting the common method of randomly perturbing the initial parameter estimates with one saddle-reset step enhances the accuracy of maximum likelihood estimates by overcoming saddle points parameter values, a common issue in nonlinear mixed-effects models. This algorithm, as implemented in the NONMEM software, was applied to various identifiable and nonidentifiable pharmacometric models, showing improved performance over traditional methods. Part of the thesis was dedicated to the development of a paediatric pharmacokinetic model for ethionamide, a drug used in treating multidrug-resistant tuberculosis. The resulting model was then used to simulate drug exposure under different dosing regimens, a new dosing regimen for children was proposed. The developed model, and therefore the proposed paediatric dosing regimen, considers factors like maturation of pharmacokinetic pathways and, administration by nasogastric tube, and concurrent rifampicin treatment. The regimen, with some modifications, was adopted in the 2022 update to the World Health Organization operational handbook on tuberculosis. Finally, the thesis explored novel model-integrated evidence (MIE) approaches for bioequivalence (BE) determination. Such methods could offer more robust alternatives to standard BE approached using non-compartmental analysis (NCA). Model-based methods have been shown to be advantageous in sparse data situations, such as is found in studies of ophthalmic formulations, but have suffered from inflated type I error rates. MIE BE approaches using a single model or

Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles.Graphical abstractAll-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.

Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli, offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-kill experiments (using strains with minimum inhibitory concentrations, MICCIP 0.023–1 mg/L and MICCST 0.5–0.75 mg/L). It was also sought to demonstrate an approach of simulating concentrations at the site of infection with population pharmacokinetic and whole-body physiologically based pharmacokinetic models to explore the clinical value of the combination when facing more resistant strains (using extrapolated strains with lower susceptibility). The combined effect in the final model was described as the sum of individual drug effects with a change in drug potency: for ciprofloxacin, concentration at half maximum killing rate (EC50) in combination was 160% of the EC50 in monodrug experiments, while for colistin, the change in EC50 was strain-dependent from 54.1% to 119%. The benefit of co-administrating a lower-than-commonly-administrated colistin dose with ciprofloxacin in terms of drug effect in comparison to either monotherapy was predicted in simulated bloodstream infections and pyelonephritis. The study illustrates the value of pharmacokinetic-pharmacodynamic modelling and simulation in streamlining rational development of antibiotic combinations.

Background: The beneficial role of glucose-dependent insulinotropic polypeptide receptor (GIPR) in weight control and maintaining glucose levels has led to the development of several multi-agonistic peptide drug candidates, targeting GIPR and glucagon like peptide 1 receptor (GLP1R) and/or the glucagon receptor (GCGR). The in vivo quantification of target occupancy by these drugs would accelerate the development of new drug candidates. The aim of this study was to evaluate a novel peptide (GIP1234), based on previously reported ligand DOTA-GIP-C803, modified with a fatty acid moiety to prolong its blood circulation. It would allow higher target tissue exposure and consequently improved peptide uptake as well as in vivo PET imaging and quantification of GIPR occupancy by novel drugs of interest. Method: A 40 amino acid residue peptide (GIP1234) was synthesized based on DOTA-GIP-C803, in turn based on the sequences of endogenous GIP and Exendin-4 with specific amino acid modifications to obtain GIPR selectivity. A palmitoyl fatty acid chain was furthermore added at Lys14 via a glutamic acid linker to prolong its blood circulation time by the interaction with albumin. GIP1234 was conjugated with a DOTA chelator at the C -terminal cysteine residue to achieve 68Ga radiolabeling. The resulting PET probe, [68Ga]Ga-DOTA-GIP1234 was evaluated for receptor binding specificity and selectivity using HEK293 cells transfected with human GIPR, GLP1R, or GCGR. Blocking experiments with tirzepatide (2 mu M) were conducted using huGIPR HEK293 cells to investigate binding specificity. Ex vivo and in vivo organ distribution of [68Ga]Ga-DOTA-GIP1234 was studied in rats and a pig in comparison to [68Ga]Ga-DOTA-C803-GIP. Binding of [68Ga]Ga-DOTA-GIP1234 to albumin was assessed in situ using polyacrylamide gel electrophoresis (PAGE). The stability was tested in formulation buffer and rat blood plasma. Results: [68Ga]Ga-DOTA-GIP1234 was synthesized with non-decay corrected radiochemical yie, The last two authors contributed equally

An orally administered bilayer tablet with Tamsulosin (TAM) as the sustained release (SR) and Finasteride (FIN) as immediate release (IR) was manufactured. A response surface methodology was employed to formulate bilayer tablets with individual release layers, i.e., sustained and immediate release (SR and IR). Independent variables selected in both cases comprise hydroxypropyl methylcellulose (HPMC) as SR polymer, and avicel PH102 in the inner layer while Triacetin and talc in the outer layer, respectively. Tablets were prepared by direct compression, a total of 11 formulations were prepared for inner layer TAM, and 9 formulations for outer layer FIN were designed; these formulations were evaluated for hardness, friability, thickness, %drug content, and %drug release. A central composite design was employed in response surface methodology to design and optimize the formulation. The percentage of drug released was evaluated by in-vitro USP dissolution method of optimized formulation for 0.5, 2, and 6 hrs, and results were 24.63, 52.96, and 97.68 %, respectively. Drug release data was plotted in various kinetic models using a D.D solver, where drug release was first order that is concentration dependent and was best explained by Korsmeyer–Peppa kinetics, as the highest linearity was observed (R2 = 0.9693). However, a very close relationship was also noted with Higuchi kinetics (R2 = 0.9358). The mechanism of drug release was determined through the Korsmeyer model, and exponent "n" was found to be 0.4, indicative of an anomalous diffusion mechanism or diffusion coupled with erosion.

Efficient drug delivery remains a critical challenge for treating neurodegenerative diseases, such as Alzheimer's disease (AD). Using innovative nanomaterials, delivering current medications like acetylcholinesterase inhibitors to the brain through the intranasal route is a promising strategy for managing AD. Here, we developed a unique combinational drug delivery system based on N,N,N-trimethyl chitosan nanoparticles (NPs). These NPs encapsulate rivastigmine, the most potent acetylcholinesterase inhibitor, along with insulin, a complementary therapeutic agent. The spherical NPs exhibited a zeta potential of 17.6 mV, a size of 187.00 nm, and a polydispersity index (PDI) of 0.29. Our findings demonstrate significantly improved drug transport efficiency through sheep nasal mucosa using the NPs compared to drug solutions. The NPs exhibited transport efficiencies of 73.3% for rivastigmine and 96.9% for insulin, surpassing the efficiencies of the drug solutions, which showed transport efficiencies of 52% for rivastigmine and 21% for insulin ex vivo. These results highlight the potential of a new drug delivery system as a promising approach for enhancing nasal transport efficiency. These combinational mucoadhesive NPs offer a novel strategy for the simultaneous cerebral delivery of rivastigmine and insulin, which could prove helpful in developing effective treatments of AD and other neurodegenerative conditions.

Background Chemotherapy-induced peripheral neuropathy (CIPN) represents a major unmet medical need that currently has no preventive and/or curative treatment. This is, among others, driven by a poor understanding of the contributive role of drug transport across biological barriers to target-site exposure. Methods Here, we systematically investigated the transport of 11 small-molecule drugs, both, associated and not with CIPN development, at conventional (dorsal root ganglia, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN sites. We developed a Combinatory Mapping Approach for CIPN, CMA-CIPN, combining in vivo and in vitro elements. Results Using CMA-CIPN, we determined the unbound tissue-to-plasma concentration ratio (K-p,K-uu) and the unbound intracellular-to-extracellular concentration ratio (K-p,K-uu,K-cell), to quantitatively assess the extent of unbound drug transport across endothelial interfaces and parenchymal cellular barriers of investigated CIPN-sites, respectively, in a rat model. The analysis revealed that unique pharmacokinetic characteristics underly time-dependent accumulation of the CIPN-positive drugs paclitaxel and vincristine at conventional (dorsal root ganglia and sciatic nerve) and non-conventional (skeletal muscle) CIPN sites. Investigated CIPN-positive drugs displayed intracellular accumulation contrary to CIPN-negative drugs nilotinib and methotrexate, which lacked this feature in all investigated tissues. Conclusions Hence, high unbound drug intracellular and extracellular exposure at target sites, driven by an interplay of drug transport across the endothelial and parenchymal cellular barriers, is a predisposing factor to CIPN development for CIPN-positive drugs. Critical drug-specific features of unbound drug disposition at various CIPN- sites provide invaluable insights into understanding the pharmacological/toxicological effects at the target-sites which will inform new strategies for monitoring and trea

Many dinoflagellates of the genus Alexandrium are well known for being responsible for harmful algal blooms (HABs), producing potent toxins that cause damages to other marine organisms, aquaculture, fishery, tourism, as well as induce human intoxications and even death after consumption of contaminated shellfish or fish. In this review, we summarize potential bioprospecting associated to the genus Alexandrium, including which Alexandrium spp. produce metabolites with anticancer, antimicrobial, antiviral, as well as anti-Alzheimer applications. When available, we report their mechanisms of action and targets. We also discuss recent progress on the identification of secondary metabolites with biological properties favorable to human health and aquaculture. Altogether, this information highlights the importance of studying which culturing conditions induce the activation of enzymatic pathways responsible for the synthesis of bioactive metabolites. It also suggests considering and comparing clones collected in different locations for toxin monitoring and marine bioprospecting. This review can be of interest not only for the scientific community, but also for the entire population and industries.

Hirudins, natural sulfo(glyco)proteins, are clinical anticoagulants that directly inhibit thrombin, a key coagulation factor. Their potent thrombin inhibition primarily results from antagonistic interactions with both the catalytic and non-catalytic sites of thrombin. Hirudins often feature sulfate moieties on Tyr residues in their anionic C-terminus region, enabling strong interactions with thrombin exosite-I and effectively blocking its engagement with fibrinogen. Although sulfotyrosines have been identified in various hirudin variants, the precise relationship between sulfotyrosine and the number of negatively charged amino acids within the anionic-rich C-terminus peptide domain for the binding of thrombin has remained elusive. By using Fmoc-SPPS, hirudin dodecapeptides homologous to the C-terminus of hirudin variants from various leech species were successfully synthesized, and the effect of sulfotyrosine and the number of negatively charged amino acids on hirudin-thrombin interactions was investigated. Our findings did not reveal any synergistic effect between an increasing number of sulfotyrosines or negatively charged amino acids and their inhibitory activity on thrombin or fibrinolysis in the assays, despite a higher binding level toward thrombin in the sulfated dodecapeptide Hnip_Hirudin was observed in SPR analysis., QC 20240209

Hypothesis: The stabilization and isolation to dryness of drug nanoparticles has always been a challenge for nano-medicine production. In the past, the use of montmorillonite (MMT) clay carrier particles to adsorb drug nanoparticles and maintain their high surface area to volume ratio after isolation to dryness has proven to be effective. We hypothesise that the distribution of hydrophilic and hydrophobic patches on the clay's surface as well as its porosity/roughness, hinder the agglomeration of the drug nanoparticles to the extent that they retain their high surface area to volume ratio and display fast dissolution profiles. Experiments: In this work, the distribution of hydrophobicity and hydrophilicity, and the porosity/roughness, of the surface of selected silica carrier particles were varied and the impact of these variations on drug nanoparticle attachment to the carrier particle and subsequent dissolution profiles was studied. Findings: The fastest dissolution profiles at the highest drug nanoparticle loadings were obtained with a periodic mesoporous organosilane carrier particle which had a homogeneous distribution of hydrophobic and hydrophilic surface properties. Carrier particles with rough/porous surfaces and a combination of hydrophobic and hydrophilic patches resulted in nanocomposite powders with faster dissolution behaviour than carrier particles with predominantly either a hydrophobic or hydrophilic surface, or with non-porous/smoother surfaces., QC 20240125

Semaglutide is the first oral glucagon-like peptide-1 (GLP-1) analog commercially available for the treatment of type 2 diabetes. In this work, semaglutide was incorporated into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NPs) to improve its delivery across the intestinal barrier. The nanocarriers were surface-decorated with either a peptide or an affibody that target the human neonatal Fc receptor (hFcRn), located on the luminal cell surface of the enterocytes. Both ligands were successfully conjugated with the PLGA-PEG via maleimide-thiol chemistry and thereafter, the functionalized polymers were used to produce semaglutide-loaded NPs. Monodisperse NPs with an average size of 170 nm, neutral surface charge and 3% of semaglutide loading were obtained. Both FcRn-targeted NPs exhibited improved interaction and association with Caco-2 cells (cells that endogenously express the hFcRn), compared to non-targeted NPs. Additionally, the uptake of FcRn-targeted NPs was also observed to occur in human intestinal organoids (HIOs) expressing hFcRn through microinjection into the lumen of HIOs, resulting in potential increase of semaglutide permeability for both ligand-functionalized nanocarriers. Herein, our study demonstrates valuable data and insights that the FcRn-targeted NPs has the capacity to promote intestinal absorption of therapeutic peptides., QC 20240202

There are examples in the literature demonstrating different approaches to defining the item characteristic functions (ICF) and characterizing the latent variable time-course within a pharmacometrics item response theory (IRT) framework. One such method estimates both the ICF and latent variable time-course simultaneously, and another method establishes the ICF first then models the latent variable directly. To date, a direct comparison of the "simultaneous" and "sequential" methodologies described in this work has not yet been systematically investigated. Item parameters from a graded response IRT model developed from Parkinson's Progression Marker Initiative (PPMI) study data were used as simulation parameters. Each method was evaluated under the following conditions: (i) with and without drug effect and (ii) slow progression rate with smaller sample size and rapid progression rate with larger sample size. Overall, the methods performed similarly, with low bias and good precision for key parameters and hypothesis testing for drug effect. The ICF parameters were well determined when the model was correctly specified, with an increase in precision in the scenario with rapid progression. In terms of drug effect, both methods had large estimation bias for the slow progression rate; however, this bias can be considered small relative to overall progression rate. Both methods demonstrated type 1 error control and similar discrimination between model with and without drug effect. The simultaneous method was slightly more precise than the sequential method while the sequential method was more robust towards longitudinal model misspecification and offers practical advantages in model building.

1-(2,3-Dihydro-1H-inden-5-yl)-2-(piperidin-1-yl)pentan-1-one (3,4-Pr-PipVP), a novel synthetic cathinone (SCat), was first identified in 2022 in Germany. The product was marketed as 1-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-2-(pyrrolidin-1-yl)pentan-1-one (3,4-EtPV), a substance not covered by the German New Psychoactive Substances Act (NpSG). Although originally intended to be an exploratory new synthetic cathinone containing the novel bicyclo[4.2.0]octatrienyl function, the compound was subsequently confirmed to contain an indanyl ring system scheduled under generic legislation like the NpSG. However, it is one of only a few marketed SCats carrying a piperidine ring. Inhibition experiments involving norepinephrine, dopamine, and serotonin transporters showed that 3,4-Pr-PipVP was a low potency blocker at all three monoamine transporters compared to related substances such as MDPV. Additionally, pharmacokinetic data were collected from pooled human liver microsomes incubations and from the analysis of authentic urine samples received after oral administration of 5 mg 3,4-Pr-PipVP hydrochloride. Phase I metabolites were tentatively identified in vitro and in vivo using liquid chromatography-time-of-flight mass spectrometry. Main metabolites were formed by metabolic reduction of the carbonyl function with and without additional hydroxylations at the propylene bridge of the molecule. Keto-reduced H-2-3,4-Pr-PipVP and H-2-piperidine-OH-3,4-Pr-PipVP as well as aryl-OH-3,4-Pr-PipVP, and indanyl-OH-piperidine-OH-3,4-Pr-PipVP are suggested as most suitable biomarkers for the detection of 3,4-Pr-PipVP since they were detected for much longer than the parent compound. 3,4-Pr-PipVP could be detected for up to 21 h whereas its metabolites were detectable for up to about 4 days., Funding Agencies|Internal Security Fund of the European Union [IZ25-5793-2019-33]

Many new psychoactive substances (NPS) are stimulants, and information about their potency and abuse potential is often lacking. To start addressing this need, a method measuring the inhibition of the dopamine, serotonin, and norepinephrine transporters (DAT, SERT, and NET) by stimulant drugs was developed. The use of a proprietary fluorescent dye mixture and three cell lines (CHO-K1, HEK 293, and MDCK), each expressing a single transporter, allowed for a semiautomated, one-pot determination of inhibition in a 384-well format. The method was validated using well characterized stimulants, including cocaine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), & alpha;-PVP, and fluoxetine and performed similarly to other methods. Seven synthetic cathinones all showed highest potency for DAT inhibition, followed by NET and SERT. The rank potency for DAT inhibition IC50 (nM) was MPHP (4.53) > 4Cl-& alpha;-PVP (8.05) > 3F-& alpha;-PVP (12.7) > & alpha;-PiHP (13.4) > N-ethylpentylone (16.9) > N-ethylhexedrone (44.5) > 4-methylpentedrone (261). All but 4-methylpentedrone were more potent than amphetamine (257) and cocaine (111). The DAT/SERT inhibition ratio for the cathinones was in the range from 5.02 for 4-methylpentedrone to >3730 for & alpha;-PiHP, compared to 1.64 for cocaine and >4030 for & alpha;-PVP. All seven substances had inhibition profiles similar to those of potent stimulants with high abuse potential., Funding Agencies|Public Health Agency of Sweden; National Board of Forensic Medicine

Doping is defined as the use of prohibited substances or methods by the World Anti-Doping Agency and the aim with doping control analysis is to detect the use of these illicit substances or methods. Substances that are prohibited in human or equine sports have either a positive or negative impact on the performance. Since administered drugs generally are metabolized to a varying degree and thereby not only excreted in their original form, their metabolite profiles are of high interest because drug metabolites may be present in the body for a longer time than the administered drug itself. Thereby detection of metabolites can improve the window of detection. Unfortunately, the metabolite profiles of non-approved drugs that are mainly available on the Internet, such as Selective Androgen Receptor Modulators (SARMs) are often unknown. This thesis consists of four papers that all encompass drug metabolite profiling either in vivo, in vitro or in a combination, utilizing separation with liquid chromatography and detection with high resolution mass spectrometry. In paper I and II, the equine in vivo metabolite profiles of the two SARMs ACP-105 and LGD-3303 were investigated and the results showed that using drug metabolites as analytical targets can prolong the detection time. For ACP-105, the in vivo metabolite profile was compared with different incubation models such as liver microsomes, S9 fractions and the fungus Cunninghamella elegans. The in vivo and in vitro metabolite profiles showed an interesting overlap for several metabolites, demonstrating the importance and usefulness for in vitro methods in doping control, especially since microsome incubates are allowed as reference material. An optimization of microsome incubation conditions utilizing experimental design was presented in paper III and IV, showing that the optimized conditions greatly impacted the yield of drug metabolites, but also that the optimal conditions are substance dependent. In paper III, a mult

While tuberculosis is a global pandemic, hemophilia is a rare disease which many have not heard of. Due to tuberculosis mainly being a problem in developing countries and hemophilia being a rare disease, they are not as heard of as other diseases such as cancer or metabolic diseases which are on the rise in Western societies. The quality of life for patients suffering from these diseases is notably impaired and novel drugs are warranted to further improve the treatment and management of both diseases. As market incentives are a limiting factor, it is important that the efforts that are taken to develop novel drugs are carried out in an informative manner. One strategy to incorporate as much information as possible to inform decision making in drug development is to use pharmacometric methods. Such strategies enable simultaneous analysis of different types of data that are generated during drug development programs. In this thesis, the aim was to develop and apply pharmacometric models to facilitate dose selection and study designs in clinical programs that aim at developing new drugs for tuberculosis and hemophilia. A standardized analysis approach of early clinical trials studying drugs against tuberculosis was presented including power calculations that showed the number of patients needed to detect drug effects. Such efforts are important as showing drug effect in early trials will aid decision making into significantly longer and costlier late trials. The approach was used to analyze a clinical trial studying if the current dose of meropenem can be lowered without negatively impacting drug effects and improving the already poor tolerability of the drug. The study found that lowering the dose may lower activity without any improvement of the tolerability properties. Furthermore, population pharmacokinetic models were developed for two novel hemostatic drugs in development for prophylactic and on-demand treatment of hemophilia. Based on the models, clinical tr

Background Biopharmaceuticals are complex biological molecules that require careful storage and handling to ensure medication integrity. In this study, a work system analysis of real-world protein drug (PD) handling was performed with the following goals: identify main barriers and facilitators for successful adherence to accepted recommendations in PD handling, analyse differences in two organisations, and define a Best Current Practice in the real-life handling of PDs based on the results of the work system analysis. Methods Observational study held in two university hospitals in Spain and Sweden. Based on the Systems Engineering Initiative for Patient Safety (SEIPS) model, the tools chosen were: the PETT scan, in order to indicate the presence of barriers or facilitators for the PETT components (People, Environment, Tools, Tasks); the Tasks and tools matrices to construct a checklist to record direct observations during the real-life handling of biopharmaceuticals, and the Journey map to depict the work process.Observations were performed between March-November 2022. Each episode of direct observation included a single protein drug in some point of the supply chain and considered all the elements in the work system. Based on the results of the work system analysis and the literature review, the authors propose a list of items which could be assumed as Best Current Practice for PDs handling in hospitals. Results There were a total of 34 observations involving 19 PDs. Regarding People involved in the work process, there was a diversity of professionals with different previous training and knowledge, leading to an information gap. With respect to Environment, some structural and organizational differences between hospitals lead to risks related to the time exposure of PDs to room temperature and mechanical stress. Some differences also existed in the Tools and Tasks involved in the process, being especially relevant the lack of compatibility information of PDs with

Interspecies scaling of the pharmacokinetics (PK) of CB 4332, a 150 kDa recombinant complement factor I protein, was performed using traditional and model-based approaches to inform first-in-human dose selection. Plasma concentration versus time data from four preclinical PK studies of single intravenous and subcutaneous (SC) CB 4332 dosing in mice, rats and nonhuman primates (NHPs) were modeled simultaneously using naive pooling including allometric scaling. The human-equivalent dose was calculated using the preclinical no observed adverse effect level (NOAEL) as part of the dose-by-factor approach. Pharmacokinetic modeling of CB 4332 revealed species-specific differences in the elimination, which was accounted for by including an additional rat-specific clearance. Signs of anti-drug antibodies (ADA) formation in all rats and some NHPs were observed. Consequently, an additional ADA-induced clearance parameter was estimated including the time of onset. The traditional dose-by-factor approach calculated a maximum recommended starting SC dose of 0.9 mg/kg once weekly, which was predicted it to result in a trough steady-state concentration lower than the determined efficacy target range for CB 4332 in humans. Model simulations predicted the efficacy target range to be reached using 5 mg/kg once weekly SC dosing., Title in the list of papers of Rami Ayoun Alsoud's thesis: Model-based allometric scaling approaches for predicting human pharmacokinetics of CB 4332, a therapeutic complement factor I protein

Poorly soluble drugs represent a substantial portion of emerging drug candidates, posing significant challenges for pharmaceutical formulators. One promising method to enhance the drug’s dissolution rate and, consequently, bioavailability involves transforming them into an amorphous state within mesoporous materials. These materials can then be seamlessly integrated into personalized drug formulations using Additive Manufacturing (AM) techniques, most commonly via Fused Deposition Modeling. Another innovative approach within the realm of AM for mesoporous material-based formulations is semi-solid extrusion (SSE). This study showcases the feasibility of a straightforward yet groundbreaking hybrid 3D printing system employing SSE to incorporate drug-loaded mesoporous magnesium carbonate (MMC) into two different drug formulations, each designed for distinct administration routes. MMC was loaded with the poorly water-soluble drug ibuprofen via a solvent evaporation method and mixed with PEG 400 as a binder and lubricant, facilitating subsequent SSE. The formulation is non-aqueous, unlike most pastes which are used for SSE, and thus is beneficial for the incorporation of poorly water-soluble drugs. The 3D printing process yielded tablets for oral administration and suppositories for rectal administration, which were then analyzed for their dissolution behavior in biorelevant media. These investigations revealed enhancements in the dissolution kinetics of the amorphous drug-loaded MMC formulations. Furthermore, an impressive drug loading of 15.3 % w/w of the total formulation was achieved, marking the highest reported loading for SSE formulations incorporating mesoporous materials to stabilize drugs in their amorphous state by a wide margin. This simple formulation containing PEG 400 also showed advantages over other aqueous formulations for SSE in that the formulations did not exhibit weight loss or changes in size or form during the curing process post-printing. These r

Transient permeation enhancers (PEs) have been widely used to improve the oral absorption of macromolecules. During pharmaceutical development, the correct selection of the macromolecule, PE, and the combination needs to be made to maximize oral bioavailability and ensure successful clinical development. Various in vitro and in vivo methods have been investigated to optimize this selection. In vitro methods are generally preferred by the pharmaceutical industry to reduce the use of animals according to the "replacement, reduction, and refinement" principle commonly termed "3Rs," and in vitro methods typically have a higher throughput. This paper compares two in vitro methods that are commonly used within the pharmaceutical industry, being Caco-2 and an Ussing chamber, to two in vivo models, being in situ intestinal instillation to rats and in vivo administration via an endoscope to pigs. All studies use solution formulation of sodium caprate, which has been widely used as a PE, and two macromolecules, being FITC-dextran 4000 Da and MEDI7219, a GLP-1 receptor agonist peptide. The paper shares our experiences of using these models and the challenges with the in vitro models in mimicking the processes occurring in vivo. The paper highlights the need to consider these differences when translating data generated using these in vitro models for evaluating macromolecules, PE, and combinations thereof for enabling oral delivery.

Conformal prediction has seen many applications in pharmaceutical science, being able to calibrate outputs of machine learning models and producing valid prediction intervals. We here present the open source software CPSign that is a complete implementation of conformal prediction for cheminformatics modeling. CPSign implements inductive and transductive conformal prediction for classification and regression, and probabilistic prediction with the Venn-ABERS methodology. The main chemical representation is signatures but other types of descriptors are also supported. The main modeling methodology is support vector machines (SVMs), but additional modeling methods are supported via an extension mechanism, e.g. DeepLearning4J models. We also describe features for visualizing results from conformal models including calibration and efficiency plots, as well as features to publish predictive models as REST services. We compare CPSign against other common cheminformatics modeling approaches including random forest, and a directed message-passing neural network. The results show that CPSign produces robust predictive performance with comparative predictive efficiency, with superior runtime and lower hardware requirements compared to neural network based models. CPSign has been used in several studies and is in production-use in multiple organizations. The ability to work directly with chemical input files, perform descriptor calculation and modeling with SVM in the conformal prediction framework, with a single software package having a low footprint and fast execution time makes CPSign a convenient and yet flexible package for training, deploying, and predicting on chemical data. CPSign can be downloaded from GitHub at https://github.com/arosbio/cpsign.

The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin-meropenem combination therapy in carbapenem-resistant Gram-negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic-pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting Acinetobacter baumannii isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model-predicted growth at 24 h of ≥ 2-log10 (164/207) correlated positively with clinical failure (adjusted odds ratio, aOR = 2.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti-infective PKPD data can be integrated through pharmacodynamic modeling and identify patient- and pathogen-specific factors related to clinical outcomes - an approach that may improve understanding of study outcomes.

Structure-based virtual screening aims to find molecules forming favorable interactions with a biological macromolecule using computational models of complexes. The recent surge of commercially available chemical space provides the opportunity to search for ligands of therapeutic targets among billions of compounds. This review offers a compact overview of structure-based virtual screens of vast chemical spaces, highlighting successful applications in early drug discovery for therapeutically important targets such as G protein-coupled receptors and viral enzymes. Emphasis is placed on strategies to explore ultra-large chemical libraries and synergies with emerging machine learning techniques. The current opportunities and future challenges of virtual screening are discussed, indicating that this approach will play an important role in the next-generation drug discovery pipeline.

The purpose of this work is to use post compression in-die cyclic loading as an analytical powder compression tool. Cyclic loading experiments (partial unloading followed by reloading) were performed on tablets formed from three relatively coarse powders (similar to 100 mu m) comprised of microcrystalline cellulose (MCC), ibuprofen (IBU) and lactose monohydrate (LAC). The reloading curve was always linear initially, irrespective of the shape of the unloading curve. Hence, nonlinearities in the unloading curve should be attributed to inelastic phenomena rather than to nonlinear elasticity. The slope of the reloading curve generally decreased with increasing degree of unloading, indicating a progressive damage of the contact network upon unloading. For MCC and IBU, consistent unloading curves following primary and secondary loading were obtained. For LAC, the secondary unloading curves were displaced towards smaller tablet heights, suggesting that that particle fragmentation occurs during unloading and reloading, also when the maximal tableting pressure is not exceeded.

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies.

Introduction: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. Methods: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. Results: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 mu g/g (IQR: 21.94-60.65 mu g/g) in skin and 33.29 mu g/mL (IQR: 25.9-42.58 mu g/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. Conclusion: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.

Chemically induced, targeted protein degradation with proteolysis targeting chimeras (PROTACs) has shown to be a promising pharmacological strategy to circumvent the poor "druggability" of intracellular targets. However, the favorable pharmacology comes with complex molecular properties limiting the oral bioavailability of these drugs. To foster the translation of PROTACs into the clinics it is of high importance to establish sensitive bioanalytical methods that enable the assessment of absorption, bioavailability, and disposition of PROTACs after oral dosing. In this study, two highly sensitive LC-MS/MS methods (LLOQ = 0.5 ng/mL) were developed and validated for the quantification of bavdeglutamide (ARV-110) and vepdegestrant (ARV-471) in rat plasma. Plasma samples were processed by protein precipitation and separated on a C18 column over a gradient of acetonitrile and water with 0.1 % formic acid. Selected reaction monitoring in positive ESI mode was applied to quantify ARV-110 and ARV-471. Both methods showed linearity, accuracy, and precision as well as matrix effects and carry-over within the predefined acceptance criteria. High stability of the compounds in plasma was demonstrated at long-term storage for seven weeks at-20°C, three freeze-thaw cycles, up to 20 min at room temperature, and as extracts in the autosampler. The plasma concentration-time curves after intravenous and intraduodenal bolus single-dose administrations in rats could be successfully quantified at clinically relevant doses per body weight. The highly sensitive bioanalytical assays presented in this work enable the application of a broad spectrum of in vivo studies to elucidate the oral absorption, bioavailability, and disposition of PROTACs.

Drug delivery techniques based on polymers have been investigated for their potential to improve drug solubility, reduce systemic side effects, and controlled and targeted administration at infection site. In this study, we developed a co-polymeric hydrogel composed of graphene sheets (GNS), polyvinyl alcohol (PVA), and chitosan (CS) that is loaded with methotrexate (MTX) for in vitro liver cancer treatment. Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM) was employed to check the structural properties and surface morphology. Moreover, tests were conducted on the cytotoxicity, hemolytic activity, release kinetics, swelling behaviour and degradation of hydrogels. A controlled release of drug from hydrogel in PBS at pH 7.4 was examined using release kinetics. Maximal drug release in six hours was 97.34%. The prepared hydrogels did not encourage the HepG2 growth and were non-hemolytic. The current study highlights the potential of GNS-based hydrogel loaded with MTX as an encouraging therapy for hepatocellular carcinoma. HepG2 cell viability of MTX-loaded CS-PVA-GNS hydrogel was (IC50 5.87 mu g/200 mL) in comparison to free MTX (IC50 5.03 mu g/200 mL). These outcomes recommend that hydrogels with GNS ensure improved drug delivery in cancer microenvironment while lessening adverse consequences on healthy cells.

Läkarna på barnavdelningen på Vrinnevisjukhuset upplevde utmaningar kring förskrivning av licensläkemedel. Detta resulterade i merarbete för läkarna samt att barnens medicinuthämtning på apotek fördröjdes. Licensläkemedel innebär att barnläkaren ansöker om att använda en läkemedelsbehandling som inte finns registrerad för barn i Sverige. Detta involverar vårdgivare, läkemedelsverket och apotek. Projektledaren fick möjlighet att leda ett projektarbete med två kliniska farmaceuter och sju barnläkare för att förbättra samverkan mellan dessa aktörer. Syftet med förbättringsarbetet var att inleda en ny arbetsprocess genom att kliniska farmaceuter bidrog med stöd till läkarna i licensläkemedelsprocessen. Smarta målet var att 50 % av läkarna som ingick in arbetsgruppen skulle ta stöd av kliniska farmaceuter under perioden mätning skedde. Resultatet av förbättringsarbete blev en ny etablerad arbetsprocess som godkändes av ledningen och sattes i bruk, samt framtagande av informationsblad till vårdnadshavare för att skapa förståelse och involvering i licensprocessen. Ny arbetsprocess godkändes av ledningen och sattes i bruk där 4 av 7 läkare sökte stöd hos kliniska farmaceuter under mätningsperioden. Syftet med studien var utvärdering av förbättringsarbetet som utfördes. Studien utvärderade samspelet genom applicering av COM-b metoden som ramverk och analys av intervjuer och fältdata. Resultatet av studien visar att samspelet underlättar arbetet för läkarna, där kliniska farmaceuters genom sin breda kunskap och kommunikationsförmåga stöttar såväl läkarna, apoteket som barnen och deras familjer så att de kan få ut sin medicin i tid., Improvement work and study of interprofessional collaboration between pediatricians and clinical pharmacist in license prescription Pediatricians in the pediatric department at Vrinnevi Hospital experience challenges with prescribing license drugs, resulting in additional work for the doctors and delays in children receiving their medications from pharmacies. License medicine refers to the process where a physician seeks permission to choose a medication treatment not available in Sweden, involving healthcare providers, the Swedish medical product agency, and pharmacies. The author had the opportunity to lead this project. The improvement effort involved a team consisting of seven pediatricians and two clinical pharmacists, The aim of quality improvement project was to initiate and involve an established method where pharmacists could provide support to doctors by with the help of new work flow. The SMART goal was for 50% of the doctors in the focus group to seek support from clinical pharmacists during the measurement period. Results of the improvement work was a newly established workflow that was approved by the management and applied, along with the creation of information sheets that invite guardians to understand the licensing process. The aim of study was evaluating the interaction through the implementation of the COM-B method and the analysis of interviews and field data. Result of the empirical findings show that collaboration took place where clinical pharmacists and pediatrists, through their extensive knowledge and communication skills, support both the care, the pharmacy, and also help patients to obtain their medicine on time.

Postpartum depression is a condition that displays symptoms such as insomnia, anxiety, and difficulties with feeling happiness. This affects approximately 10–17 % of pregnant women and new mothers around the world. The hypothalamic-pituitary-adrenal axis (HPA-axis) and the downregulation of gamma-aminobutyric acid (GABA) signaling are believed to be a part of the pathology behind postpartum depression, although it is currently not known in detail what causes the condition to develop. Women with postpartum depression are believed to have a hyperactive HPA-axis due to an increased sensitivity to estrogen and progesterone. If postpartum depression is left untreated, there could be severe consequences. For example, women who have had postpartum depression have a three times higher risk of death than those who have not encountered the condition. There could also be consequences for the newborn since there is for instance a risk of impaired cognitive ability among children whose mother has had postpartum depression. Psychological treatment consists of cognitive behavior therapy and interpersonal therapy among others. Today there is no approved medication in Sweden for the indication postpartum depression but there is two in the US, brexanolone and zuranolone. Brexanolone is administered by intravenous infusion, which limits the patient to hospital treatment. Zuranolone is a synthetic molecule that is designed to imitate the neurosteroid allopregnanolone as an agonist for the GABAa-receptor. It is the first medication for the indication that is administered orally. The mechanism of action is not fully elucidated but zuranolone binds to GABAa-receptors, upregulates the expression of GABA-receptors and increases GABA-signaling. The purpose of this literature study was to evaluate the safety and efficacy of zuranolone for the treatment of postpartum depression. Five relevant clinical studies were collected from the database PubMed. The results show a statistically significan, Förlossningsdepression är ett tillstånd som ger symtom som sömnsvårigheter, ångest och att känna sig nedstämd. Detta beräknas drabba ca 10–17% av alla gravida eller nyblivna mammor världen över. Det är inte helt klarlagt vad tillståndet beror på men det tros ha en koppling till bl.a. hypotalamus-hypofysbinjure-axeln (HPA-axeln) och en nedreglering av gamma-amino-smörsyra(GABA)-signalering. HPAaxeln tros vara överaktiv på grund av ökad känslighet för hormonerna östrogen och progesteron hos patienter med förlossningsdepression. Sjukdomen kan ge negativa effekter för både kvinnan och barnet, till exempel ses en tre gånger högre dödsrisk hos mammor som haft förlossningsdepression och en risk för nedsatt kognitiv förmåga hos barnet vars mamma haft förlossningsdepression. Förlossningsdepression kan ibland behandlas psykologiskt med exempelvis kognitiv beteendeterapi (KBT) eller interpersonell terapi (IPT) men ibland också med läkemedel. I Sverige finns ännu inget godkänt läkemedel med indikationen men i USA finns det två, brexanolon samt zuranolon. Brexanolon ges som intravenös infusion vilket begränsar patienten till sjukhusinläggning. Zuranolon är en syntetisk molekyl som efterliknar neurosteroiden allopregnanolon och är det första läkemedlet med indikationen förlossningsdepression som ges peroralt. Dess verkningsmekanism är delvis okänd men zuranolon binder in till GABAa-receptorer och uppreglerar uttrycket av GABA-receptorer samt ökar GABAsignalering. Syftet med denna litteraturstudie var att undersöka om zuranolon är en säker och effektiv behandling vid förlossningsdepression. Detta gjordes genom en artikelsökning via databasen PubMed där fem relevanta kliniska studier valdes ut. Studierna visade att zuranolon är en effektiv behandling då preparatet visade en statistiskt signifikant skillnad jämfört med placebo på flera självskattningsskalor, som Hamilton Rating Scale for Depression (HRSD-17), Hamilton Rating Scale for Anxiety (HRSA) och MontgomeryÅsberg Depression

This study investigates the efficacy of a newly developed humanized serum-free media (SFM) that replaces Fetal Bovine Serum (FBS), in culturing of common in vitro models (Caco-2 and 3D Primary Human Hepatocytes (PHH)). The research’s focus aligns with the 3R principles (replacement, reduction, refinement) and may potentially lead to enhancing the human relevance of the in vitro models and ultimately contribute to more accurate and successful drug development in the future. This study is divided into two subprojects, Caco-2 and 3D PHH, respectively. For Caco-2, we evaluated cell morphology, proliferation and monolayer formation by assessing the permeability of marker compounds. For PHH, we investigated spheroid formation and viability using an ATP measurement assay, lipid concentration using an Adipored Assay and CYP activity of the 3D PHH. Finally, global proteomics analysis was performed for both Caco-2 cells and 3D PHH grown in SFM and in conventional medium (CM). Our findings show that Caco-2 cells could proliferate well enough in the SFMCaco-2 without any change in their cell morphology, whereas their monolayer tightness was found to be similar in SFMCaco-2 as compared to CMCaco-2. Furthermore, from the proteomics analysis there was no major difference detected between cells in SFMCaco-2 and in CMCaco-2, however several of the relevant drug transporters of this model were found in higher levels in Caco-2 cultured in SFMCaco-2. For 3D PHH, our findings indicate that spheroids could be perfectly formed in both SFM3D PHH and in CM3D PHH, having relatable viability and lipid concentration, especially after two week of culturing period. Finally, the proteomics analysis revealed no significant difference between the proteome of the spheroids when cultured in SFM3D PHH or in CM3D PHH. In conclusion, these results suggest that the SFM provides a viable and sometimes superior alternative to CM for both Caco-2 and 3D PHH, promoting the 3R principles and potentially offeri

The path to patient access post-market approval is anything but straightforward. While some medications seamlessly find their way to those in need, others encounter significant obstacles. Biopharmaceuticals offer benefits in the treatment of many diseases. However, the adoption of these new biological medicines varies widely across European countries in view of often high costs. Despite the significant growth in approvals and economic expansion observed in the biopharmaceutical market, there are few cross-national comparative studies focused on the utilization of biologics to provide future guidance. Objective The study aimed to better understand the disparities in the early diffusion of new biologics across Europe. The research questions included identifying the extent of data availability and variations in the early diffusion of biopharmaceuticals across European countries, as well as investigating macro-level factors influencing their early diffusion. Methods A cross-sectional study was undertaken to analyze the diffusion patterns of 17 biopharmaceuticals, approved between 2015 and 2019, across European countries between 2015 and 2022. The study addressed data availability, diffusion rates, measured with Defined Daily Doses per 1000 population and relative rankings between countries to assess the early diffusion over the initial four years following market authorization. Additionally, macro-level factors influencing early diffusion were identified by meetings with policy researchers and experts. Results Data availability varied, 12 out of 29 countries provided complete data on inpatient and outpatient care, 10 provided limited data, and 7 provided no data. The introduction patterns varied between medicines, with Tildrakizumab and Follitropin delta being introduced in the least number of countries. Germany, Norway, Denmark, and Sweden demonstrated the highest early diffusion rates, while Estonia, Scotland, Romania, and Lithuania had the lowest. Three majo

Background: Antidepressant medications are widely prescribed in Sweden, yet comprehensivelongitudinal studies examining trends in their utilization over time are scarce. This thesisaddresses this gap by exploring the patterns of antidepressant drug utilization in Sweden from1977 to 2023. Aims: The primary aim of this study is to investigate the longitudinal trends in antidepressantutilization across different demographic groups, including age and gender, and various categoriesof antidepressants. Methods: A quantitative-descriptive repeated cross-sectional design is employed, utilizingaggregated sales data from 1977 to 2000 and prescription data from 2006 to 2023. Defined DailyDose per 1000 inhabitants per day (DDD/TID) and Patients per 1000 inhabitants are used asprincipal analytical metrics. The study population comprises all men and women of all ages whoobtained at least one prescription for antidepressants during the study period. Results: The analysis reveals a notable escalation in antidepressant consumption over the studyperiod. Sales statistics indicate a significant increase in antidepressant usage from approximately6 DDD/TID in 1977 to 48 DDD/TID by 2000. Prevalence data from 2006 to 2023 shows a rise inpatients per 1000 inhabitants, reaching 114 in 2023, with women receiving more prescriptionsthan men nearly doubling that of men by 2023. Selective Serotonin Reuptake Inhibitors(SSRIs)(N06AB) experienced a significant increase between 1992 and 2000, while TricyclicAntidepressants (TCAs) declined gradually. Other antidepressants (N06AX) also showed a slowincrease, competing with SSRIs by 2023. Antidepressant usage was higher among adults,particularly those over 60, compared to younger individuals. Conclusion: This thesis underscores the evolving landscape of antidepressant drug utilization inSweden, highlighting the need for tailored interventions to address demographic-specific patternsand optimize mental health care delivery.

This thesis evaluates Item Response Theory (IRT) models in pharmacometrics, focusing on their application to clinical outcome assessments (COAs). In the research of IRT on COAs, there is a lack of criteria to decide if a COA is good or not, besides, few studies has been done to investigate the impact of using different structural models on a COA. Thus, the first part of the study compares the characteristic of 9 COAs, including their distribution of fisher information, discrimination and difficulty parameters, and the second part is about the comparison between Graded Response Model (GRM) and the Generalized Partial Credit Model (GPCM) across multiple COAs including the Scale for the Assessment and Rating of Ataxia (SARA) and the Expanded Disability Status Scale (EDSS), in which the analysis about GRM and GPCM includes real and simulated datasets to assess model performance, based on aspects such as Item Characteristic Curves (ICCs), Fisher information, discrimination parameters, difficulty parameters, the predictions (PSIs), longitudinal effect and power. From the first part of the study, an initial criterion for the comparison between different COAs is established, which can be used to evaluate if a COA is better than the other in terms of its parameters and fisher information. The findings of the second part indicate that while both models are useful, GPCM provides more higher information for certain range of disease severity, whereas GRM offers broader consistency and generalizability. This research contributes to better informing the decision-making in designing the COAs as well as the choice of IRT structural models to analyze COA data.

Background: Attentiveness is a fundamental function of the brain. Deficits in attentional performance is a major cause for individual and societal burden. An important region involved in attention is striatum, inside of which there is dopamine: a key neurotransmitter in the regulation of attention. The dopamine transporter (DAT) is abundant in dorsal striatum (DS) and ventral striatum (VS) and DAT acts as a modulator of dopamine signaling. Abnormal DAT expression is identified as one of the causes of attentional dysfunction in several neuropsychiatric diseases. This project aimed to parse the relationship between DAT expression and attentional performance in a sustained visual attention task, as well as DAT’s relationship to amphetamine (AMPH) sensitivity. Methods: To test for attention 15 male Sprague-Dawley rats were trained and tested in a signal detection task (SDT) to gather attentional data and to measure change in performance after AMPH administration. To quantify DAT in striatum, this project used immunohistochemistry to measure fluorescent intensity, a measurement representing the corresponding DAT expression level. To support findings, the project used drift diffusion models (DDMs) to enhance our understanding of the decision-making process affected by DAT expression. Results: The results showed non-significant correlations between DAT density in DS and VS and premature responses and accuracy in the SDT. The data also showed that the DAT DS:VS expression ratio significantly correlates to AMPH sensitivity. Conclusion: We concluded that increased DAT expression in striatum can predict worse accuracy and increased premature response times during a SDT. The project also found that the ratio of DAT expression in dorsal and ventral striatum can predict changes in accuracy after AMPH administration.

The focus in the field of machine learning has increasingly shifted towards data-centric approaches, recognizing that the quality of data is crucial for the effectiveness of the models developed. One significant challenge that can degrade data quality is the presence of outliers. Therefore, this study investigates the impact of various outlier detection algorithms on the performance of machine learning models applied to QSAR datasets. Utilizing methods such as Isolation Forest (IF), Local Outlier Factor (LOF), and One-Class Support Vector Machine (OCSVM), the aim was to explore these methods and evaluate them, identify potential outliers, and assess their influence on model predictions. The study incorporated both synthetic data and real-world datasets, including those obtained from a pharmaceutical company and benchmark datasets. The methodology involved preprocessing the data, applying outlier detection algorithms, and evaluating the models using traditional metrics like Mean Squared Error (MSE) and conformal prediction for uncertainty estimation. Results indicated that no major improvements were observed using the different algorithms and that excessive data removal led to a decline. While OCSVM showed inconsistent performance across different datasets, LOF demonstrated promising potential as a method worth further investigation. This study has even highlighted different challenges including high dimensionality, the need for hyperparameter tuning, and the limitations of current outlier detection methods. It also underscores the complexity of outlier detection in QSAR data and suggests directions for future research to improve model robustness and accuracy.

Introduction: Space exploration has been a dream of mankind since ancient times, this dream became a reality with the launch of Sputnik in 1957. Since then, significant advances in space technology have enabled humans to travel beyond the Earth's atmosphere. Although some of the health risks are well known, the effect of changes in the pharmacokinetics of drugs and their effectiveness is not yet fully understood. Aim and Method: This study aims to investigate the effect of space travel on the pharmacokinetics of antibiotics. A scoping review method was employed to investigate the changes in the pharmacokinetics of antibiotics during space travel. A search of the PubMed database was performed using the relevant terms. Inclusion criteria included available English full-text articles. A three-step selection process was employed, followed by data analysis and evaluation, to select relevant original scientific articles. Results: The findings suggest that the pharmacokinetics of some antibiotics, such as ciprofloxacin penicillin and benzylpenicillin, may not be significantly altered in microgravity environments. Further research is needed to better understand the implications of space travel on antibiotic efficacy and safety. Conclusion: Current research on the pharmacokinetic changes of antibiotics in microgravity simulations shows little change compared to Earth. However, further research is crucial to understand their bioavailability, durability, and performance in space environments, ensuring the health and safety of space travelers.

Bakgrund: Diffust storcelligt B-cellslymfom (DLBCL) är en högmalign cancersjukdom som drabbar B-lymfocyterna, en typ av vita blodkroppar. Incidensen i Sverige är omkring 600 fall per år. Utan effektiv behandling sker sjukdomsprogressionen med ett snabbt förlopp. Under de senaste två årtiondena har behandlingarna som använts i första och andra linjen kunnat bota 60–70% av patienterna med DLBCL. För patienterna som inte svarat på standardbehandlingarna är prognosen mycket allvarlig. YESCARTA är ett nytt genterapiläkemedel som består av patientens egna T-celler modifierade med en chimär antigen receptor (CAR). När CAR T-cellen binder till B-lymfocyter frisätts inflammatoriska mediatorer som orsakar celldöd av både normala och tumöromvandlade B-lymfocyter. Syfte: Hur påverkar behandling med YESCARTA den totala överlevnaden (OS), responsfrekvensen (ORR), progressionsfri överlevnad (PFS), händelsefri överlevnad (EFS), responsduration (DOR), samt komplett och partiell respons (CR & PR) hos patienter med diffust storcelligt B-cellslymfom (DLBCL)? Detta arbete syftar till att systematiskt sammanställa och utvärdera befintlig vetenskaplig litteratur om YESCARTA för att besvara denna frågeställning. Metod: Litteratursökningen utfördes i PubMed. Samtliga MeSH-termer för läkemedlet YESCARTA konsoliderades och filter för observation- och kliniska studier applicerades. Sökningen genererade 34 artiklar, varav 10 kunde inkluderas. Exklusion skedde huvudsakligen av studier som undersökt annat än den terapeutiska effekten av YESCARTA. Resultat: Majoriteten av studierna var av typen fas II. En fas III-studie med varianter i uppföljningstid och undergruppsanalys inkluderades. YESCARTA förefaller vara överlägsen standardbehandling i alla utfallsmått. Resultatet är mest robust för ORR, EFS och PFS. Cirka fyra av fem patienter kan förväntas uppnå remission efter behandling med YESCARTA. Effektfördelen av YESCARTA i OS och DOR är osäker med avseende på statistisk signifikans. Slutsats

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 group

Inledning: Attention deficit hyperactivity disorder (ADHD) är en neuropsykiatrisk funktionsnedsättning som sannolikt beror på en annorlunda struktur och funktion av det centrala nervsystemet och en annorlunda utveckling av hjärnan. Tecken på ADHD kan vara svårigheter med uppmärksamhet och koncentration, överaktivitet och impulsivitet. Prevalensen för ADHD kan variera beroende på geografiskt område, i Nordamerika är prevalensen 3 - 7 % av alla barn i skolåldern och i Europa ca 1 - 3 %. Centralstimulerande läkemedel är den vanligaste läkemedelsgruppen vid farmakologisk behandling av ADHD-symptom. Lisdexamfetamin (LDX) är en prodrug till amfetaminderivatet dextroamfetamin, som blockerar återupptag samt ökar utsöndringen av dopamin och noradrenalin. LDX finns i Sverige under namnet Elvanse. Syfte: Nuvarande studie syftade till att undersöka effekt och säkerhet av lisdexamfetamin (Elvanse) för behandling av barn och tonåringar. Metod: Arbetet var en litteraturstudie där fem vetenskapliga artiklar valdes ut i den vetenskapliga databasen pubMed. Kriterier för artiklarna var att de skulle vara randomiserade kontrollerade studier som genomgått peer review. Artiklarna skulle behandla intag av lisdexamfetamin till barn och målet var att hitta studier med så unga deltagare som möjligt. Studier med vuxna uteslöts och likaså studier vars syfte var att jämföra LDX mot ett annat läkemedel. Resultat: Primärt utfall var en skillnad på grad av symptom enligt skalan ADHD-RS-IV i fyra av studierna och samtliga visade en förbättring jämfört med placebo. Flera olika skalor användes för sekundärt utfall och även dessa visade en förbättring vid intag av LDX jämfört med placebo. En av studierna var en post hoc-analys som visade en förbättring av emotionell labilitet hos deltagarna med intag av LDX. Inga nya allvarliga händelser upptäcktes. De vanligaste biverkningarna var liknande de typiska för amfetamin; minskad aptit, insomnia, övre buksmärtor, huvudvärk, irritabilitet och viktnedgång. Sl, Introduction: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder. ADHD likely depends on a different structure and function of the central nervous system and a dissimilar brain development. The condition is often characterized by inattention, hyperactivity, and impulsive behavior. The core symptoms are associated with impairments in academic, social, and intrapersonal functioning. ADHD and intelligence do not correlate. Comorbidity is more frequent among people with ADHD; the most common among children are learning disabilities and problems with conduction and defiance. Among adults, more comorbid severe mental disorders such as anxiety, depression, suicidal thoughts, and attempted or completed suicide occur. Different types of abuse are more common among adolescents and adults with ADHD. Studies show that ADHD is hereditary, but exactly how is not clarified. It is probably a combination of several genetic and environmental factors that cause symptoms of ADHD to be expressed. The prevalence of ADHD can vary depending on the geographical area. In North America, the prevalence is 3 – 7 % of all school-age children, and in Europe, about 1 – 3 %. Stimulants are the most common type of drug for pharmacological treatment of ADHD symptoms. Lisdexamfetamine (LDX) is a long-acting prodrug stimulant. It requires enzymatic hydrolysis to yield the therapeutically active metabolite D-amfetamine, which blocks reuptake and increases the secretion of dopamine and norepinephrine. LDX is available in Sweden under the name Elvanse. Aim: This literature study aimed to investigate the efficacy and safety of LDX (Elvanse) in children and adolescents. Methods: Five scientific articles were selected from the scientific database PubMed. Inclusion criteria were that the articles should be randomized controlled trials undergone peer review, and the study population should include children. Key exclusion criteria were studies on adults and studies that compared LD