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  • 1.
    Abass Abdulkadir, Sazan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Use of a Clinical Decision Support System to Identify Potential Drug-Related Problems: Focused on the Types of Alerts for Pediatric Patients2022Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background: Sweden is among the top countries with the greatest use of e-prescriptions at a national level. A clinical decision support system called Electronic Expert Support (EES) is available at all pharmacies in Sweden to examine e-prescriptions in connection with the dispensing to prevent drug related problems (DRPs). DRPs result in patient suffering and substantial costs for society. The types of alerts generated for pediatric patients at Swedish pharmacies using EES-system has not been studied before, to the best of our knowledge. Aim: The aim of this research is to study the use of EES at pharmacies in Sweden for the pediatric population (ages 0-12 years), by describing what types of alerts for potential DRPs are generated, how they are handled and how the use of EES has changed over time. Method: Data on the number and categories of EES analyses, alerts, and resolved alerts was provided by the Swedish eHealth Agency. Results: The study shows that the use of EES has increased. The most common type of generated alert for a potential DRP among pediatric was high dose pediatric (30,3% of all alerts generated). The most common type of alert for a potential DRP that was resolved among pediatrics was therapy duplication (45,8%). The most common reason for closing an alert was dialogue with patient for verification of the treatment (66,3% of all closed alerts). Conclusion: Knowledge of which type of alerts that are the most common may contribute to increased prescriber awareness of important potential DRPs. Future studies should investigate the clinical relevance of the generated alerts for the pediatric population.

  • 2.
    Abass Abdulkadir, Sazan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Fac Pharm, Dept Pharm, S-75237 Uppsala, Sweden..
    Wettermark, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Fac Pharm, Dept Pharm, S-75237 Uppsala, Sweden..
    Hammar, Tora
    Linnaeus Univ, eHlth Inst, Dept Med & Optometry, S-39182 Kalmar, Sweden..
    Potential Drug-Related Problems in Pediatric Patients-Describing the Use of a Clinical Decision Support System at Pharmacies in Sweden2023In: Pharmacy, E-ISSN 2226-4787, Vol. 11, no 1, article id 35Article in journal (Refereed)
    Abstract [en]

    The clinical support system Electronic Expert Support (EES) is available at all pharmacies in Sweden to examine electronic prescriptions when dispensing to prevent drug-related problems (DRPs). DRPs are common, and result in patient suffering and substantial costs for society. The aim of this research was to study the use of EES for the pediatric population (ages 0-12 years), by describing what types of alerts are generated for potential DRPs, how they are handled, and how the use of EES has changed over time. Data on the number and categories of EES analyses, alerts, and resolved alerts were provided by the Swedish eHealth Agency. The study shows that the use of EES has increased. The most common type of alert for a potential DRP among pediatric patients was regarding high doses in children (30.3% of all alerts generated). The most common type of alert for a potential DRP that was resolved among pediatrics was therapy duplication (4.6% of the alerts were resolved). The most common reason for closing an alert was dialogue with patient for verification of the treatment (66.3% of all closed alerts). Knowledge of which type of alerts are the most common may contribute to increased prescriber awareness of important potential DRPs.

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  • 3.
    Abass, mariam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mortalitet bland covid-19 antikoagulantia användare patienter och icke-antikoagulantia användare: en systematisk översikt2022Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Covid-19 is a serious infectious disease that was first discovered in China in 2019. The disease spread very quickly, infecting over 40 million globally and leading to more than a million deaths. The damage caused by the corona infection led to severe thromboembolic conditions that led to death. Therefore, anticoagulants were used in connection with corona to prevent the thromboembolic conditions. But has the use of anticoagulants in covid-19 patients really affected mortality?    Aim: To make a systematic review that explores whether anticoagulant use among COVID-19 patients affect mortality.    Methods: A systematic search was conducted September in 2022 of published studies on PubMed associated with mortality and use of anticoagulants in covid-19 patients. The articles reviewed were selected based on defined PICO and inclusion and exclusion criteria. Types of studies reviewed were cohort and case-control studies.    Results & conclusions:   A total of 20 different studies were studied and based on them it is concluded that anticoagulant treatment associated with lower mortality in severely ill covid-19 patients has been demonstrated. However, bleeding risk was observed in other covid-19 patients due to use of anticoagulants.

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  • 4.
    Abdaljaleel, Ghofran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Tablettillverkning genom användning av torrgranulering (valspressning)2020Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
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  • 5.
    Abdallah, Nadia Younous
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rekommenderade dygnsdoser för barn - Går det att beräkna?2021Independent thesis Basic level (degree of Bachelor), 12 HE creditsStudent thesis
    Abstract [en]

    Background: Defined daily dose (DDD) is a unit that gives an estimate of drug utilization. The DDDs that are developed today are only based on adult’s drug use. That means that the DDDs for adults may not necessarily apply to children. 

    Aim: To calculate recommended daily dose for boys and girls in different ages and compare it with DDD for adults for paracetamol, phenoxymethylpenicillin, desloratadine and melatonin.  

    Methods: This descriptive cross-sectional study was conducted September-October 2021. Boys and girls in ages 1, 5, 12 and 16 years were included. Data was retrieved from FASS.se, tillväxtkurvor.se and WHO Collaborating Centre for Drug Statistics Methodology. 

    Results: The children’s daily doses are lower than DDD for adults for paracetamol for all ages, phenoxymethylpenicillin for ages 1, 5 and 12 and desloratadine for ages 1 and 5. The daily doses of phenoxymethylpenicillin aged 16 are higher than DDD for adults. Daily doses for melatonin and desloratadine age 12 and 16 were the same as DDD for adults. Paracetamol and phenoxymethylpenicillin have variations in the daily doses for the children. Girls in all ages except from 12 years and the youngest children had lowers doses. Desloratadine ages 1 and 5 had the same dose and ages 12 and 16 had the same dose. For melatonin the children received the same doses. 

    Conclusion: The calculated recommended daily doses for children are to some extent in line with WHO DDDs. In order to use WHO DDDs in children, it is important to have knowledge of which drugs and ages they can be applied for.  

     

     

     

  • 6.
    Abdelwahab, Mahmoud Tareq
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Court, Richard
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Everitt, Daniel
    Global Alliance TB Drug Dev, New York, NY USA..
    Diacon, Andreas H.
    Stellenbosch Univ, Dept Med, Tygerberg, South Africa.;Task Appl Sci, Bellville, South Africa..
    Dawson, Rodney
    Univ Cape Town, Div Pulmonol, Lung Inst, Cape Town, South Africa.;Univ Cape Town, Dept Med, Lung Inst, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Uppsala Univ, Dept Pharm, Uppsala, Sweden..
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 7, article id e02687-20Article in journal (Refereed)
    Abstract [en]

    Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300mg daily for 3 days, followed by 100mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (DQTcF. 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with Delta QTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.

  • 7.
    Abdiwoli, Abdisalam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    pH-responsive release of proteins from colloidal capsules for oral drug delivery2020Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Biologics are an important part of modern healthcare and are mostly administered parenterally due to the fact that it is the route of administration that avoids degradation of biologics and ensures their systemic exposure. However, there is a need to develop oral drug delivery formulations for local treatment of diseases in the gastrointestinal tract (GI). Colloidal capsules is a formulation that can potentially facilitate oral administration of biologics. There have been studies on colloidal capsules and the various ways of manufacturing them, one of which is “Emulsion-based method”. The aim of this study was to produce colloidal capsules made of silica nanoparticles through emulsion-based method, coat them to study their pH-responsive release and characterize them. Encapsulation of a model protein in the silica colloidal capsules was also attempted. pH-responsive release was not studied due to limited access to the laboratory and, a literature study of articles about colloidal capsules was conducted instead, regarding different aspects of colloidal capsule synthesis and encapsulation of various compunds. Web of science was the database used to find scientific studies that specifically produced colloidal capsules. Colloidal capsules were synthesized using a Pickering-emulsion method. Commercially available SiO2 nanoparticles were used to form the capsules by ultrasonication.  The hydrodynamic size and capsule morphology were analyzed using dynamic light scattering (DLS) and scanning electron microscopy (SEM), respectively. Zeta potential was measured through electrophoretic light scattering (ELS). Articles for the literature study were found using the “web of science” database. Colloidal capsules were successfully produced, coated and characterized. Additionally, the literature study shows that there diverse colloidal capsule synthesis conditions, model proteins and applications for colloidal capsules.

  • 8.
    Abdulameer, Shams
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Test och utvärdering av Janusmed Riskprofil i valideringssystemet SAPVAL vid Akademiska sjukhuset i Uppsala (System Assisted Pharmaceutical VALidation)2022Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 9.
    Abdulfattah, Amenah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Variation in blood pressure target achievement in primary care centers2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background: High blood pressure (BP) or hypertension is defined as a systolic and diastolic pressure over 140/90 mmHg. High blood pressure increases the risk for premature death, and previous research has shown that many patients do not reach targets and that there are differences between primary healthcare centers in the proportion of patient reaching targets. The reasons for these variations, however, are unknown. Aim: To investigate variations in blood pressure target achievement between primary care centers in Stockholm county and how different factors such as practice size, ownership, socioeconomic and antihypertensive drug treatment can influence this diversity. Method(s): This study was designed as a cross-sectional register study with a descriptive quantitative perspective. Data was collected from three sources: National Primary Care Quality register, Care Need Index for healthcare in Stockholm region and Stockholm County Council data warehouse VAL. The study included 179 out of all 227 primary care centers in the region. The proportion of all patients with hypertension reaching targets was assessed each year during 2019-2021, and correlations studied for potential predictors. Results: there was a variation between primary care centers in target blood pressure fulfillment, ranging from 22-66% during 2021, 23-63% during 2020 and 33-66% during 2019, respectively. There was no overall difference between public and private centers in the proportion of patients reaching targets, but a larger practice variation among private centers. No correlation was found between the other studied factors and target blood pressure fulfillment during 2021. Conclusion: There was a variation between primary care centers in the proportion of patients reaching blood pressure targets. Different practices may change ranking between years and other factors than practice size, ownership and socioeconomic appears to explain the variation.

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  • 10.
    Abdulrahim, Souad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Evaluation of UTLAM PDMS with Rotating Membrane Diffusion Cell for In Vitro Lipolysis Assay of Felodipine Loaded LBF2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The number of poorly water-soluble drugs acquiring a high lipophilicity (BCS class II) have increased tremendously in the pharmaceutical development pipeline over the past decades. One of the solutions that has been conducted to overcome the low aqueous solubility problem was to co-administer these drugs with lipids or fats as lipid-based formulations (LBF). In vitro lipid digestion assays for drug loaded LBF have been used to predict the behaviour of these drugs in vivo in the GI tract. The aim of this study was to examine the feasibility of using Ultra-Thin Large Area PDMS membrane of (~10 μm) thickness with Rotating Membrane Diffusion Cell (RMDC) for in vitro lipolysis-permeation experiments for Felodipine loaded Lipid-based Formulation. Membrane fabrication was done using Sylgard 184 elastomer kit and spin-coater device to get the ultra-thin membranes of approximately 10 μm thickness. Felodipine loaded LBF (22mg/g Felodipine, LBF type: MC-IIIA) was digested in the RMDC at 100 rpm speed for 60 min at 37°C. 75 μl of Lucifer Yellow (10 mM) was used as a membrane integrity marker and was added to the donor chamber of (225 mL) volume prior to digestion to check for mass transfer through the membrane in the receiver chamber (70 mL). During the digestion phase, the maximum ionised fatty acids was 0.402 mmol at 59.6 min, however, the unionised fatty acids during back titration have reached 0.86 at 61.4 min. Lucifer Yellow mass transfer graphs showed a steady increase in the area under the curve at the time point 20 min, where it reached approximately 75 nmol min cm-2. The experiment needs to be repeated to be able to identify a more rigorously justified leak criterion for LY-PDMS. It should be noted that PDMS-LY partition experiments were planned, so that the partitioning affinity could be determined to predict the flux of Lucifer Yellow through PDMS. This secondary method would provide a priority leak criterion.

  • 11. Abrahamsson, B
    et al.
    Lennernas, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Application of the biopharmaceutic classification system now and in the future2003In: Drug Bioavailability – Estimation of Solubility, Permeability, Absorption and Bioavailability, Wiley , 2003Chapter in book (Other scientific)
  • 12.
    Abrahamsson, B.
    et al.
    AstraZeneca R&D, S-43183 Molndal, Sweden..
    McAllister, M.
    Pfizer, Tadworth, Surrey, England..
    Augustijns, P.
    Katholieke Univ Leuven, Leuven, Belgium..
    Zane, P.
    Sanofi Aventis, Paris, France..
    Butler, J.
    GSK, Brentford, England..
    Holm, R.
    Johnson & Johnson, Machelen, Belgium..
    Langguth, P.
    Johannes Gutenberg Univ Mainz, Mainz, Germany..
    Lindahl, A.
    Med Prod Agcy, Uppsala, Sweden..
    Muellertz, A.
    Univ Copenhagen, Copenhagen, Denmark..
    Pepin, X.
    United Kingdom, AstraZeneca R&D, Cambridge, England..
    Rostami-Hodjegan, A.
    Certara, London, England.;Univ Manchester, Manchester, Lancs, England..
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Berntsson, M.
    AstraZeneca R&D, S-43183 Molndal, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project2020In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 152, p. 236-247Article in journal (Refereed)
    Abstract [en]

    OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.

  • 13. Abrams, Pascale
    et al.
    Boquete, Hugo
    Fideleff, Hugo
    Feldt-Rasmussen, Ulla
    Jonsson, J
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wilton, Patrick
    Abs, Roger
    GH replacement in hypopituitarism improves lipid profile and quality of life independently of changes in obesity variables2008In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 159, no 6, p. 825-832Article in journal (Refereed)
    Abstract [en]

    Objective: GH deficiency (GHD) in adults is characterized by elevated body mass index (BMI), increased waist girth (WG) and increased fat mass (FM). Information about how these indicators of obesity affect the lipid profile and quality of life (QoL) of GHD subjects is scarce. It is also unclear how changes in these indicators brought about by GH replacement influence lipids and QoL. Design and methods: Adult GHD Subjects from the Pfizer International Metabolic Database were grouped according to BMI (n = 291 with BMI < 25 kg/m(2), n = 372 with BMI 25-30 kg/m(2), n = 279 with BMI > 30 kg/m(2)), WG (n = 508 with normal WG, n = 434 with increased WG) and FM (n = 357) and according to changes in these variables after 1 year of GH replacement. Serum IGF-1 concentrations, lipid concentrations and QoL using the QoL Assessment of GHD in Adults questionnaire were assessed at baseline and after 1 year of treatment. Results: At baseline, total and low-density lipoprotein (LDL) cholesterol were similarly elevated in the BMI and WG groups, but high-density lipoprotein (HDL) cholesterol decreased and triglycerides increased with increasing BMI and WG. QoL was progressively poorer with increasing BMI and WG. After 1 year of GH replacement, total and LDL cholesterol and QoL improved in all BMI, WG and FM groups. Conclusions: Variables of obesity adversely affect the already unfavourable lipid profile in GHD Subjects by decreasing HDL cholesterol, but do not counteract the positive effect of GH replacement on LDL cholesterol. Similarly, QoL is influenced by obesity, but responds equally well to GH treatment independent of BMI, WG and FM.

  • 14.
    Abramsson, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Use of heart failure medications in elderly people and association with cognitive impairment2022Independent thesis Advanced level (degree of Master (One Year)), 10 credits / 15 HE creditsStudent thesis
  • 15.
    Abrantes, João
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Solms, Alexander
    Bayer, Berlin, Germany.
    Garmann, Dirk
    Bayer, Wuppertal, Germany.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patientsIn: Article in journal (Refereed)
  • 16. Abs, Roger
    et al.
    Feldt-Rasmussen, Ulla
    Mattsson, Anders F
    Monson, John P
    Bengtsson, Bengt-Ake
    Goth, M I
    Wilton, Patrick
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis.2006In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 155, no 1, p. 79-90Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of the present study was to clarify the relationship between GH deficiency (GHD) andsome cardiovascular risk factors and to analyse the effect of GH replacement therapy in a large numberof patients over a prolonged period of time.Design: Data for analysis were retrieved from KIMS (Pfizer International Metabolic Database). Serumconcentrations of total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein(LDL)-cholesterol and triglycerides were obtained from 2589 patients at baseline and from 1206patients after 1 and 2 years of GH replacement therapy. Body mass index (BMI), waist and hip, restingblood pressure and body composition were also measured.Results: At baseline, the unfavourable effects of GHD were most obvious in the lipid profiledemonstrating elevated mean total and LDL-cholesterol, in the increased waist circumference and theelevated BMI. The cholesterol concentration, BMI and body composition were significantly adverselyaffected by a number of factors, including age, sex and the use of anti-epileptic drugs. The therapeuticeffect of GH was essentially uniform across the whole population. GH replacement reduced significantlythe mean total and LDL-cholesterol, the waist circumference and the fat mass and was maintainedduring 2 years.Conclusions: This analysis of a large number of patients confirmed that GHD adults present with anincreased cardiovascular risk. The sustained improvement of the adverse lipid profile and bodycomposition suggests that GH replacement therapy may reduce the risk of cardiovascular disease andthe premature mortality seen in hypopituitary patients with untreated GHD.

  • 17. Abs, Roger
    et al.
    Mattsson, Anders F
    Bengtsson, Bengt-Ke
    Feldt-Rasmussen, Ulla
    Goth, Miklos I
    Koltowska-Häggström, Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Monson, John P
    Verhelst, Johan
    Wilton, Patrick
    Isolated growth hormone (GH) deficiency in adult patients: Baseline clinical characteristics and responses to GH replacement in comparison with hypopituitary patients. A sub-analysis of the KIMS database.2005In: Growth Horm IGF Res, ISSN 1096-6374, Vol. 15, no 5, p. 349-59Article in journal (Refereed)
  • 18.
    Abu Madi, Bayan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Uttrappning av läkemedel vid behandling av neuropatisk smärta: I detta projektarbete var syftet att hitta evidensbaserade studier som beskriver uttrappningsstrategier för gabapentin, pregabalin och amitriptylin.2022Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
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  • 19.
    Adane, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gebre-Mariam, T
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The use of extragranular disintegrants in multiple-unit tablet formulations: effect on compressibility, compactibility and disintegration2007In: Journal of drug delivery science and technology, ISSN 1773-2247, Vol. 17, no 4, p. 279-284Article in journal (Refereed)
    Abstract [en]

    Multiple-unit tablets formed from mixtures of microcrystalline cellulose pellets and disintegrants (Ac-Di-Sol, Primojel or Kollidon CL) by compaction were investigated with the aim of controlling tablet tensile strength and disintegration time. The effects of pellet porosity, compaction pressure, and type and amount of disintegrant were studied. Primojel made the pellets less prone to deformation during compression, while the other two disintegrants had very minor effects on the compression behavior. Ac-Di-Sol and Primojel generally increased the tablet tensile strength, whereas the effect of Kollidon CL was dependent on the initial pellet porosity. Kollidon CL was found to significantly reduce the disintegration time, but the other two disintegrants had variable efficacy, and for the low-porosity pellets significantly increased the disintegration time. These results are interpreted as resulting from the interplay between the mechanical characteristics of the pellets and the mechanisms of action of the disintegrants.

  • 20.
    Adjil Khoder, Valentina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Prevalence of hepatotoxicity in pediatric oncology patients with intracranial or extracranial solid tumors: A retrospective, cohort study2024Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Abstract

    Background: Out of approximately 1,6 million children in Sweden, about 350 are diagnosed with cancer each year. Chemotherapeutic agents are commonly used in the treatment of various cancer types in pediatric oncology. While it is established that certain chemotherapeutic agents induce hepatotoxicity as a side effect, a comprehensive assessment of the prevalence of hepatotoxicity in pediatric oncology populations has been lacking.

    Aim: This study aims to investigate the prevalence of hepatotoxicity in pediatric patients between 0-18 years with intracranial and extracranial solid tumors. 

    Method: A retrospective cohort study was conducted, at Uppsala University Children’s Hospital. Data regarding administered chemotherapeutic treatment and liver values such as alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP), bilirubin and lactate dehydrogenase (LD), were collected over a 4-month period from start of treatment. Tto identify the treatment cycle in which hepatotoxicity occurred the data were divided into treatment cycles. During each treatment cycle, the liver values were collected on day 1, 8, 15, 22 or adjacent days. For patients experiencing hepatotoxicity, it was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. 

    Results: Fifty patients were included, and the study yielded four main findings: 1) Approximately 30% of pediatric oncology patients experienced hepatotoxicity, 2) Treatment adjustments were implemented, such as dose reduction and treatment pause, for those with grade 3 and 4 toxicity, 3) Hepatotoxicity tends to exhibit a higher prevalence in males, 4) Hepatotoxicity tends to exhibit a higher prevalence in younger children. 

    Conclusion: The observed prevalence of hepatotoxicity exceeded initial expectations, with approximately 30% suffer from hepatotoxicity due to chemotherapeutic treatment. However, future studies with larger sample size are needed. 

  • 21.
    Adolfsson, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Caramella, C
    Nystrom, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    The effect of milling and addition of dry binder on the interparticulate bonding mechanisms in sodium chloride tablets1998In: Int J Pharmaceutics, Vol. 160, p. 187-Article in journal (Refereed)
  • 22.
    Adolfsson, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Gustafsson, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Nystrom, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Use of tablet tensile strength adjusted for surface area and mean interparticulate distance to evaluate dominating bonding mechanisms1999In: DRUG DEV IND PHARMACY, Vol. 25, p. 753-Article in journal (Refereed)
  • 23.
    Adolfsson, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Nystrom, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Tablet strength, porosity, elasticity and solid state structure of tablets compressed at high loads1996In: INTERNATIONAL JOURNAL OF PHARMACEUTICS, Vol. 132, p. 95-Article in journal (Refereed)
  • 24.
    Adolfsson, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Olsson, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Nystrom, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Effect of particle size and compaction load on interparticulate bonding structure for some pharmaceutical materials studied by compaction and strength characterisation in butanol1997In: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, Vol. 44, p. 243-Article in journal (Refereed)
  • 25.
    Adolfsson, Åsa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Mechanical strength of pharmaceutical compacts: Importance of material characteristics, particle characteristics and compaction pressure on interparticulate bonding structure1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Factors considered important for the interparticulate bonding structure and mechanical strength of pharmaceutical compacts were studied in this thesis.

    Fractures appear to propagate mainly around rather than through grains during strength testing. Large deviations from theoretical strength values in addition to an effect of particle size were thus obtained when compaction was performed to zero porosity or obtained by extrapolation to zero porosity. When high compaction loads were used, the excess energy was to a large extent used for elastic recovery and/or alteration of the solid-state structure.

    Filtering out of weak distance forces (intermolecular forces) by compaction in a liquid with a sufficiently high dielectric constant appears to provide reliable information on interparticulate bonding mechanisms. The best correlation between physiochemical properties of the liquids and the gradual decrease in tensile strength of the compacts was achieved using the dielectric constant. The weak distance forces appeared to be screened out when the liquid compaction medium had a dielectric constant of 18. The remaining tensile strength was then believed to be the result of interparticulate bonding by solid bridges for most materials. However, for most pharmaceutical materials, weak distance forces seem to dominate. Of all the materials tested, solid bridges seemed to be the most important bonding mechanism for sodium and potassium chloride. Increasing the particle size and compaction pressure of materials with the capacity to form solid bridges seemed to facilitate the bond formation process. Addition of a dry binder or milling the particles counteracted the formation of solid bridges, probably by reducing the concentration of stress at certain points in the compact, a prerequisite for the establishment of solid bridges.

    Both the tablet surface area and the interparticulate distance may affect the proportion of external surface area participating in interparticulate bonding. For materials prone to develop solid bridges, the actual surface area involved in bond formation is more important than the space between the particles, i.e. compensation of the tensile strength of a tablet for the surface area and the mean interparticulate distance will probably not reflect the nature of the dominating bond type. However, for the other materials, ranking of the materials according to tensile strength adjusted for surface area and mean interparticulate distance gave a reflection of dominating interparticulate bonding type.

  • 26.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. OrgFarmKemi.
    Raubacher, Florian
    Karlen, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Department of Pharmacy. OrgFarmKemi.
    Jørgensen, Flemming Steen
    Andersson, Tommy B
    Masimirembwa, Collen M
    Zamora, Ismael
    Structural analysis of CYP2C9 and CYP2C5 and an evaluation of commonly used molecular modeling techniques.2004In: Drug Metab Dispos, ISSN 0090-9556, Vol. 32, no 11, p. 1218-29Article in journal (Refereed)
  • 27.
    Ahgere, Natali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Integritet och tillämpning av etiska riktlinjer på öppenvårdsapotek ur farmaceuternas perspektiv2021Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
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  • 28.
    Ahlin, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In vitro and in silico prediction of drug-drug interactions with transport proteins2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Drug transport across cells and cell membranes in the human body is crucial for the pharmacological effect of drugs. Active transport governed by transport proteins plays an important role in this process. A vast number of transport proteins with a wide tissue distribution have been identified during the last 15 years. Several important examples of their role in drug disposition and drug-drug interactions have been described to date. Investigation of drug-drug interactions at the transport protein level are therefore of increasing interest to the academic, industrial and regulatory research communities.

    The gene expression of transport proteins involved in drug transport was investigated in the jejunum, liver, kidney and colon to better understand their influence on the ADMET properties of drugs. In addition, the gene and protein expression of transport proteins in cell lines, widely used for predictions of drug transport and metabolism, was examined.

    The substrate and inhibitor heterogeneity of many transport proteins makes it difficult to foresee whether the transport proteins will cause drug-drug interactions. Therefore, in vitro assays for OCT1 and OATP1B1, among the highest expressed transport proteins in human liver, were developed to allow investigation of the inhibitory patterns of these proteins. These assays were used to investigate two data sets, consisting of 191 and 135 registered drugs and drug-like molecules for the inhibition of OCT1 and OATP1B1, respectively. Numerous new inhibitors of the transport proteins were identified in the data sets and the properties governing inhibition were determined. Further, antidepressant drugs and statins displayed strong inhibition of OCT1 and OATP1B1, respectively. The inhibition data was used to develop predictive in silico models for each of the two transport proteins.

    The highly polymorphic nature of some transport proteins has been shown to affect drug response and may lead to an increased risk of drug-drug interactions, and therefore, the OCT1 in vitro assay was used to study the effect of common genetic variants of OCT1 on drug inhibition and drug-drug interactions. The results indicated that OCT1 variants with reduced function were more susceptible to inhibition. Further, a drug-drug interaction of potential clinical significance in the genetic OCT1 variant M420del was proposed.

    In summary, gene expression of transport proteins was investigated in human tissues and cell lines. In vitro assays for two of the highest expressed liver transport proteins were used to identify previously unknown SLC transport protein inhibitors and to develop predictive in silico models, which may detect previously known drug-drug interactions and enable new ones to be identified at the transport protein level. In addition, the effect of genetic variation on inhibition of the OCT1 was investigated.

    List of papers
    1. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines
    Open this publication in new window or tab >>Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines
    Show others...
    2007 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 35, no 8, p. 1333-1340Article in journal (Refereed) Published
    Abstract [en]

    This study was designed to quantitatively assess the mRNA expression of 36 important drug transporters in human jejunum, colon, liver, and kidney. Expression of these transporters in human organs was compared with expression in commonly used cell lines (Caco-2, HepG2, and Caki-1) originating from these organs to assess their value as in vitro transporter system models, and was also compared with data obtained from the literature on expression in rat tissues to assess species differences. Transporters that were highly expressed in the intestine included HPT1, PEPT1, BCRP, MRP2, and MDR1, whereas, in the liver, OCT1, MRP2, OATP-C, NTCP and BSEP were the main transporters. In the kidney, OAT1 was expressed at the highest levels, followed by OAT3, OAT4, MCT5, MDR1, MRP2, OCT2, and OCTN2. The best agreement between human tissue and the representative cell line was observed for human jejunum and Caco-2 cells. Expression in liver and kidney ortholog cell lines was not correlated with that in the associated tissue. Comparisons with rat transporter gene expression revealed significant species differences. Our results allowed a comprehensive quantitative comparison of drug transporter expression in human intestine, liver, and kidney. We suggest that it would be beneficial for predictive pharmacokinetic research to focus on the most highly expressed transporters. We hope that our comparison of rat and human tissue will help to explain the observed species differences in in vivo models, increase understanding of the impact of active transport processes on pharmacokinetics and distribution, and improve the quality of predictions from animal studies to humans.

    Keywords
    Urinary system, Digestive system, Cell line, Established cell line, In vitro, Kidney, Liver, Gut, Human, Genetics, Gene, Carrier protein, Drug
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-11385 (URN)10.1124/dmd.107.014902 (DOI)000248200000013 ()17496207 (PubMedID)
    Available from: 2007-09-11 Created: 2007-09-11 Last updated: 2018-01-12Bibliographically approved
    2. Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs
    Open this publication in new window or tab >>Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs
    Show others...
    2009 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 12, p. 2275-2283Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to investigate the gene and protein expression profiles of important drug transporting proteins in human cell lines commonly used for studies of drug transport mechanisms. Human cell lines used to transiently or stably express single transporters (HeLa, HEK293) and leukaemia cell lines used to study drug resistance by ABC-transporters (HL-60, K562) were investigated, and compared with organotypic cell lines (HepG2, Saos-2, Caco-2 and Caco-2 TC7). For gene expression studies, real-time PCR was used, while monospecific polyclonal antibodies were generated and used to investigate protein expression by immunohistochemistry. Thirty-six transporters were studied for gene expression and nine for protein expression. The antibodies were validated using expression patterns in human tissues. Finally, the function of one ubiquitously expressed transporter, MCT1; SLC16A1 was investigated using 14C-lactic acid as a substrate. In general, the adherent cell lines (HeLa, HEK293) displayed low transporter expression and the expression patterns were barely affected by transfection. The leukaemia cell lines (K562, HL-60) and Saos-2 also had low endogenous transporter expression, while the organotypic cell lines (HepG2 and Caco-2) showed higher expression of some transporters. Comparison of gene and protein expression profiles gave poor correlations, but better agreement was obtained for antibodies with a good validation score, indicating that antibody quality was a significant variable. Importantly, the monocarboxylic acid transporting protein MCT1 was significantly expressed in all, and functional in most of the cell lines, indicating that MCT1 may be a confounding factor when the transport of small anionic drugs is investigated.

    Keywords
    Cell lines, Caco-2, HEK293, HeLa, Saos-2, HL-60, K562, HepG2, Gene expression, Protein expression, MCT1
    National Category
    Pharmaceutical Sciences
    Research subject
    Biopharmaceutics; Pharmaceutics
    Identifiers
    urn:nbn:se:uu:diva-107571 (URN)10.1124/dmd.109.028654 (DOI)000271935200002 ()19741037 (PubMedID)
    Available from: 2009-08-17 Created: 2009-08-17 Last updated: 2022-01-28Bibliographically approved
    3. Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
    Open this publication in new window or tab >>Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
    Show others...
    2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 19, p. 5932-5942Article in journal (Refereed) Published
    Abstract [en]

    The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-86815 (URN)10.1021/jm8003152 (DOI)000259760500010 ()18788725 (PubMedID)
    Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2024-04-18Bibliographically approved
    4. Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1:: predictions of metformin interactions
    Open this publication in new window or tab >>Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1:: predictions of metformin interactions
    Show others...
    2011 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, no 6, p. 400-411Article in journal (Refereed) Published
    Abstract [en]

    Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human OCT1-reference or the variants R61C, V408M, M420del and G465R were first used to study the kinetics and inhibition pattern of the OCT1 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP(+)). In the second part OCT1-mediated (14)C-metformin uptake was studied in the presence of drugs administered concomitantly with metformin. Transport studies using ASP(+) showed that the function of the variants decreased in the following order: OCT1-reference = V408M = M420del >R61C > >G465R. Variants M420del and R61C were more sensitive to drug inhibition, with IC(50) values up to 23 times lower than those of the OCT1-reference. Uptake studies using (14)C-metformin were in qualitative agreement with those using ASP(+), with the exception that a larger reduction in transport capacity was observed for M420del. Concomitantly administered drugs, such as verapamil and amitriptyline, revealed potential drug-drug interactions at clinical plasma concentrations of metformin for OCT1-M420del.

    Keywords
    OCT1, polymorphism, metformin, drug-drug intaeractions, transport protein
    National Category
    Pharmaceutical Sciences
    Research subject
    Biopharmaceutics; Pharmaceutics
    Identifiers
    urn:nbn:se:uu:diva-107572 (URN)10.1038/tpj.2010.54 (DOI)000297506500003 ()
    Available from: 2009-08-17 Created: 2009-08-17 Last updated: 2018-01-13Bibliographically approved
    5. In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions
    Open this publication in new window or tab >>In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions
    Show others...
    2012 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 2, p. 411-426Article in journal (Other academic) Published
    Abstract [en]

    To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter. The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways. Sixty-five compounds were identified as OATP1B1 inhibitors at 20 mu M. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified. Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

    Keywords
    in silico, in vitro-in vivo extrapolation, inhibition, MRP2, OATP1B1
    National Category
    Pharmaceutical Sciences
    Research subject
    Biopharmaceutics; Pharmaceutics
    Identifiers
    urn:nbn:se:uu:diva-107573 (URN)10.1007/s11095-011-0564-9 (DOI)000299506700007 ()
    Available from: 2009-08-17 Created: 2009-08-17 Last updated: 2024-04-18Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 29.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Chen, L
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Lazorova, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Chen, Ying
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Ianculescu, Alexandra G.
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Davis, Robert L.
    3Center for Health Research Southeast, Kaiser Permanente, Atlanta, USA.
    Giacomini, Kathleen M.
    Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1:: predictions of metformin interactions2011In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 11, no 6, p. 400-411Article in journal (Refereed)
    Abstract [en]

    Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human OCT1-reference or the variants R61C, V408M, M420del and G465R were first used to study the kinetics and inhibition pattern of the OCT1 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP(+)). In the second part OCT1-mediated (14)C-metformin uptake was studied in the presence of drugs administered concomitantly with metformin. Transport studies using ASP(+) showed that the function of the variants decreased in the following order: OCT1-reference = V408M = M420del >R61C > >G465R. Variants M420del and R61C were more sensitive to drug inhibition, with IC(50) values up to 23 times lower than those of the OCT1-reference. Uptake studies using (14)C-metformin were in qualitative agreement with those using ASP(+), with the exception that a larger reduction in transport capacity was observed for M420del. Concomitantly administered drugs, such as verapamil and amitriptyline, revealed potential drug-drug interactions at clinical plasma concentrations of metformin for OCT1-M420del.

  • 30.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hilgendorf, Constanze
    AstraZeneca R&D, Mölndal.
    Karlsson, Johan
    AstraZeneca R&D, Mölndal, Sweden.
    Al-Khalili Szigyarto, Cristina
    Department of Proteomics, The Royal Institute of Technology, Stockholm, Sweden.
    Uhlén, Mathias
    Department of Proteomics, The Royal Institute of Technology, Stockholm, Sweden.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs2009In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 12, p. 2275-2283Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the gene and protein expression profiles of important drug transporting proteins in human cell lines commonly used for studies of drug transport mechanisms. Human cell lines used to transiently or stably express single transporters (HeLa, HEK293) and leukaemia cell lines used to study drug resistance by ABC-transporters (HL-60, K562) were investigated, and compared with organotypic cell lines (HepG2, Saos-2, Caco-2 and Caco-2 TC7). For gene expression studies, real-time PCR was used, while monospecific polyclonal antibodies were generated and used to investigate protein expression by immunohistochemistry. Thirty-six transporters were studied for gene expression and nine for protein expression. The antibodies were validated using expression patterns in human tissues. Finally, the function of one ubiquitously expressed transporter, MCT1; SLC16A1 was investigated using 14C-lactic acid as a substrate. In general, the adherent cell lines (HeLa, HEK293) displayed low transporter expression and the expression patterns were barely affected by transfection. The leukaemia cell lines (K562, HL-60) and Saos-2 also had low endogenous transporter expression, while the organotypic cell lines (HepG2 and Caco-2) showed higher expression of some transporters. Comparison of gene and protein expression profiles gave poor correlations, but better agreement was obtained for antibodies with a good validation score, indicating that antibody quality was a significant variable. Importantly, the monocarboxylic acid transporting protein MCT1 was significantly expressed in all, and functional in most of the cell lines, indicating that MCT1 may be a confounding factor when the transport of small anionic drugs is investigated.

  • 31.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlsson, Johan
    Pedersen, Jenny M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustavsson, Lena
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Structural requirements for drug inhibition of the liver specific human organic cation transport protein 12008In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 19, p. 5932-5942Article in journal (Refereed)
    Abstract [en]

    The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.

  • 32.
    Ahmadi, Fatema
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Förbrukningen av smärtstillande läkemedel och miljörisk i region Uppsala2021Independent thesis Basic level (degree of Bachelor), 14 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Läkemedel har en stor roll i vårt liv och användning av läkemedel påverkar vår miljö. De största utsläppen av läkemedel sker efter användningen och utsöndras i urinen. Slutligen hamnar de i avloppet och vattendrag och därefter når de oss och fiskar genom vattnet. Det finns få studier om hur läkemedelsanvändningen ser ut i relation till miljörisk.

    Syfte: Syftet med denna tvärsnittsstudie var att undersöka data kring förbrukningen av NSAID och Paracetamol i relation till miljörisk.

    Metod: Studien genomfördes genom datainsamling från Socialstyrelsens statistikdatabas för smärtstillande läkemedel och E-hälsomyndigheten statistikverktyg Concise för perioden 2010–2020. Förbrukningen av paracetamol (N02BE01) och NSAID (M01A) analyserades i kg som sålts på recept, receptfritt, till sjukhus och på öppenvård-rekvisition och bedömdes i förhållande till klassifikation av miljörisk.

    Resultat: De mest använda läkemedlen var paracetamol, ibuprofen, naproxen och diklofenak. Paracetamol och ibuprofen har låg miljöfara och försumbar miljörisk. Naproxen har medium miljöfara och låg miljörisk. Miljöfara för diklofenak finns ej publicerat på regions Stockholms databas för läkemedelsmiljöpåverkan, men risken anses vara hög jämfört med andra NSAID. En stor andel av försäljningen av paracetamol, naproxen och diklofenak expedierades via recept. Förbrukningen av paracetamol, ibuprofen och naproxen har ökat medan konsumtionen av diklofenak har minskat med 71% under 2010–2020. Slutsats: Av de fyra mest använda smärtstillande läkemedel som inte är opioder, är naproxen och diklofenak skadliga för miljön eftersom de har högt respektive medium miljöfara. Det bästa alternativet är paracetamol och ibuprofen ur ett miljöperspektiv.

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  • 33.
    Ahmed, Amal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University.
    Comparison of Mean Plasma Glucose Measured using Self-Monitoring and Continuous Glucose Monitoring – a Simulation-Based Study.2022Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
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  • 34.
    Ahmed Osman, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kartläggning av följsamhetsgrad till Region Jönköpings läns rutin för dokumentation av läkemedelsförändring vid vårdcentraler inom Region Jönköping2021Independent thesis Advanced level (degree of Master (One Year)), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background and objective: Holistic patient care is dependent upon the accurate and reliable flow of information between care settings and healthcare professionals (HCP). Inaccurate medical records may increase the risk of patient harm as HCPs risk continuing to prescribe a medication that has been discontinued or re-prescribing a medication that has previously been discontinued. The aim of this project was to analyse the HCPs documentation of medical changes in the patients’ medical records and evaluate the extent of adherence to a predefined criteria within the regions guidelines at six general practices (GP) across Jönköping County.

    Study design: A retrospective observational study, reviewing 240 medical records between June-December 2019.

    Main outcome measures: The number and the type of medication changes registered, and the extent to which the documentations adhered to regional guidelines concerning the criteria of the information that ought to be included in a documentation upon a registration of a medical change.

    Results: There was an average of 63 (95% CI:53.4 – 73.2) medical changes identified across the six GPs. None of the documentations completely adhered to all points in the guideline. Follow-up plans was found to be the most omitted data point having only been mentioned in 2% of the medical changes. The name of the prescribed medication was mentioned on 378 occasions however, it was only accompanied with dosage form on 44% of occasions. In 9% of the medical records that were analysed it was not found to include any medical changes at all, instead it was either filled in with a “0” or the HCPs had for instance confirmed that the patients’ prescriptions had been renewed.

    Conclusions: Despite the clear guidance regarding the content of documentation for a medical change, no documentation followed the guidelines fully. Adherence to the guidelines may be enhanced by being easier to access for HCPs. As there were documents that were not classed as medical changes identified, the information regarding what is acceptable to be included in that section needs to be made clearer to the HCPs. The findings from this study can be further developed and used as a reference for future studies on this subject.

  • 35. Ahmed, Sara
    et al.
    Schwartz, Carolyn
    Ring, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sprangers, Mirjam A. G.
    Applications of health-related quality of life for guiding health care: advances in response shift research2009In: Journal of Clinical Epidemiology, ISSN 0895-4356, E-ISSN 1878-5921, Vol. 62, no 11, p. 1115-1117Article in journal (Refereed)
  • 36.
    Ahnfelt, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In vitro evaluation of formulations used in the treatment of hepatocellular carcinoma2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hepatocellular carcinoma (HCC) causes ~ 600,000 deaths annually, making it the second most deadly cancer form. HCC is classified into five stages and for the intermediate HCC treatment, the two most commonly used drug delivery systems (DDSs) are lipiodol-based emulsions and drug-eluting beads. The aims of this thesis were to develop in vitro methods suitable for studying these DDSs. It is important to investigate the release mechanisms and release rates with relevant in vitro methods, as this can improve the understanding of the in vivo performance. Miniaturized in vitro methods with sample reservoirs separated from the release medium by a diffusion barrier were developed and shown to be suitable for studying drug release from particle DDSs (Paper I). In Paper II these methods were further developed and used to study the release of doxorubicin (DOX) from the clinically used drug-eluting beads. DOX release rates were affected by the method set-up and the characteristics of the release medium. The choice of method and volume of release medium could improve the in vivo-likeness of the in vitro release profiles. Applied theoretical models suggested a film-controlled type of DOX release mechanism from the beads when self-aggregation, DOX-bead interaction, and DOX deprotonation were taken into account.

    A micropipette-assisted microscopy method was used to further improve the understanding of the release mechanism of amphiphilic molecules from the beads (Paper III). A detailed analysis suggested an internal depletion-layer model dependent on molecular self-aggregation for the release. It was further suggested that a simple ion-exchange mechanism is unrealistic in physiological conditions.

    The important pharmaceutical factors for the emulsion-based formulations were investigated in Paper IV. DOX solubility, lipid phase distribution, and emulsion stability increased when the contrast agent iohexol was added. Also, an increase in release half-life (h) was observed from emulsions with iohexol.

    The in vitro methods and theoretical models presented in this thesis can be used during development and optimization of future DDSs.

    List of papers
    1. A miniaturized in vitro release method for investigating drug-release mechanisms
    Open this publication in new window or tab >>A miniaturized in vitro release method for investigating drug-release mechanisms
    2015 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, no 1-2, p. 339-349Article in journal (Refereed) Published
    Abstract [en]

    We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

    Keywords
    In vitro release methods, Release mechanisms, Weibull function, GI-Sim, In vivo prediction
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-255064 (URN)10.1016/j.ijpharm.2015.03.076 (DOI)000353999100037 ()25843760 (PubMedID)
    Available from: 2015-06-22 Created: 2015-06-12 Last updated: 2018-10-30Bibliographically approved
    2. In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
    Open this publication in new window or tab >>In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
    2016 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, p. 3387-3398Article in journal (Refereed) Published
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

    Keywords
    controlled release, diffusion, dissolution, dissolution rate, drug-delivery systems, in vitro models, mathematical model, microspheres
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-311211 (URN)10.1016/j.xphs.2016.08.011 (DOI)000388268200018 ()27663384 (PubMedID)
    Funder
    Swedish Research Council, 521-2011-373
    Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-10-30Bibliographically approved
    3. Single bead investigation of a clinical drug delivery system – a novel release mechanism
    Open this publication in new window or tab >>Single bead investigation of a clinical drug delivery system – a novel release mechanism
    Show others...
    2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, p. 235-247Article in journal (Refereed) Published
    Abstract [en]

    Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS.

    It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface (‘film control’). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.

    Keywords
    Microgel, Drug delivery, Release mechanism
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-360988 (URN)10.1016/j.jconrel.2018.11.011 (DOI)000452348100019 ()30419268 (PubMedID)
    Funder
    Swedish Research Council, 521-2011-373
    Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2022-04-18Bibliographically approved
    4. In vitro evaluation of lipiodol-based emulsions in clinical use
    Open this publication in new window or tab >>In vitro evaluation of lipiodol-based emulsions in clinical use
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-360987 (URN)
    Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-10-30
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  • 37.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Al-Tikriti, Yassir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Single bead investigation of a clinical drug delivery system – a novel release mechanism2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, p. 235-247Article in journal (Refereed)
    Abstract [en]

    Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS.

    It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface (‘film control’). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.

    Download full text (pdf)
    fulltext
  • 38.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Degerstedt, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lilienberg, Elsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In vitro evaluation of lipiodol-based emulsions in clinical useManuscript (preprint) (Other academic)
  • 39.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Degerstedt, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lilienberg, Elsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality2019In: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, article id UNSP 101143Article in journal (Refereed)
    Abstract [en]

    Transarterial chemoembolization with emulsion-based formulations using doxorubicin hydrochloride (DOX) and Lipiodol (R) is the golden standard for the loco-regional treatment of unresectable hepatocellular carcinoma (HCC). However, from a pharmaceutical quality perspective these emulsions are poorly characterized. In this study, clinically relevant Lipiodol (R)-based emulsions were characterized in terms of emulsion stability, continuous phase classification and droplet-size distribution. Also, the solubility of DOX in the different emulsion components and the distribution of DOX to the lipid phase were investigated. These are key features to investigate due to the claimed tumor-seeking properties of Lipiodol (R). The in vitro release of DOX was studied in a miniaturized dialysis method and an empirical release model was applied to adjust for the passage of DOX across the dialysis membrane. The most stable emulsion ( > 72 h) was classified as water-in-oil (w/o), had the highest distribution of DOX to the lipid phase (20%) and an aqueous-to-lipid phase ratio of 1:4. The composition of the aqueous phase was a mixture (v/v) of iohexol (85%) and water (15%). Emulsions containing iohexol and a high aqueousto-lipid phase ratio (1:2-1:4) displayed prolonged in vitro release profiles of DOX. This study further emphasizes the medical need to standardize these emulsion-based drug delivery systems.

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  • 40.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Axén, N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A miniaturized in vitro release method for investigating drug-release mechanisms2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, no 1-2, p. 339-349Article in journal (Refereed)
    Abstract [en]

    We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

    Download full text (pdf)
    fulltext
  • 41.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, p. 3387-3398Article in journal (Refereed)
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

  • 42.
    Akash, Ahlam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A study of clofazimine pharmacokinetics in Indonesian patients with multidrug-resistant tuberculosis (MDR-TB) using population modelling.2023Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Abstract

    Background Clofazimine is a repurposed drug to treat multidrug-resistant tuberculosis (MDR-TB) and is also a cornerstone of leprosy treatment. Pharmacokinetic (PK) data of clofazimine is scarce, but a population pharmacokinetics (popPK) model of clofazimine developed on data from South African MDR-TB patients has been published. Body composition was reported to be the key covariate that impacted both drug disposition and exposure. 

    Aim The aim of this master research work was to re-evaluate and optimize the published popPK model of clofazimine in Indonesian patients with MDR-TB.

    Methods The pre-existing model from South Africa was used as starting point and fitted to PK data from Indonesian, 49 patients with clofazimine based treatment over 4 months. The model was evaluated and adjusted to optimize its performance. The PK parameters were estimated and accumulation of clofazimine was examined. 

    Results The model estimated a large central volume of 100 L and a clearance of 11.7 L/h, the median terminal half-life was about 20 days and substantial accumulation was observed over the 4 months. Women had much longer half-life and thereby slower accumulation and lower exposures due to high body fat in comparison with men. A large variability between occasions and subjects was detected.

    Conclusion The model was able to describe the central tendency of the data well, but overpredicted the random variability between patients. That could be a results of participants adherence issues or varying food intake along with the drug during the treatment. This should be investigated in future analyses to get more reliable results.

  • 43.
    Akbari, Rukhsara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Absorption av levotyroxin och omeprazol eftergastric bypass – en litteraturstudie2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: Gastric bypass är en operationsmetod som leder till en fysiologisk förändring i magtarmkanalen av perorala läkemedel, i syfte till att främja viktnedgång. Tidigare studier har stärkt teorin om att ett förändrat upptag av två vanligt förekommande läkemedel i kliniken, levotyroxin och omeprazol, sker som en följd av gastric bypass operation. Absorptionen av dessa läkemedel är kliniskt relevanta då den terapeutiska effekten är avgörande för behandlingen och därmed hälsan hos en bred patientgrupp inom sjukvården. 

    Syfte: Syftet med denna litteraturstudie är att reda ut hur absorptionen av levotyroxin och omeprazol påverkas efter en gastric bypass operation. 

    Metod: Detta är en litterturstudie baserat på åtta orginalstudier, fyra om läkemedlet omeprazol och fyra studier om läkemedlet levotyroxin. Artiklarna identifierades efter sökningar i PubMed och Embase under april 2021. Inklusionskriterier var gastric bypass som operationsmetod samt att publikationsdatumet är inom de senaste 20 åren. Barn, äldre och patienter med samtidigt vitaminkonsumtion exkluderades. 

    Resultat: Av levotyroxinartiklarna konkluderar två av dessa att en minskad absorption av läkemedlet sker efter gastric bypass. De två resterande artiklar redovisade ingen förändring gällande absorptionen. Artiklar som studerade levotyroxin upptaget i form av flytande beredning efter gastric bypass, påvisade ökat läkemedelsupptag i flytande form gentemot tablettform. I de fyra artiklar som studerades omeprazol och dess absorption, styrktes en minskad läkemedlsabsorption i två av de artiklarna, samt en observerad avsaknad av signifikant skillnad i de två resterande artiklarna. 

    Slutsats: Ett fullständigt svar till frågeställningen om levotyroxin coh omeprazol leder till minskat läkemedelsupptag efter gastric bypass, kan inte återfås av denna litterturstudie på grund av motstridiga resultat. Detta resultat indikerar däremot behovet av en individuell farmakoterapi då variationen mellan olika individer gällande faktorer såsom BMI och kön, kan påverka läkemedelsupptaget. 

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  • 44.
    Akrong, Grace
    et al.
    INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France..
    Chauzy, Alexia
    INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France..
    Aranzana-Climent, Vincent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France..
    Lacroix, Mathilde
    INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France.;Inst ROCHE, Boulogne Billancourt, France..
    Deroche, Luc
    INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France..
    Prouvensier, Laure
    INSERM U1070, Poitiers, France.;CHU Poitiers, Dept Toxicol & Pharmacocinet, Poitiers, France..
    Buyck, Julien M.
    INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France..
    Couet, William
    INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France.;CHU Poitiers, Dept Toxicol & Pharmacocinet, Poitiers, France..
    Marchand, Sandrine
    INSERM U1070, Poitiers, France.;Univ Poitiers, Poitiers, France.;CHU Poitiers, Dept Toxicol & Pharmacocinet, Poitiers, France..
    A New Pharmacokinetic-Pharmacodynamic Model To Characterize the Inoculum Effect of Acinetobacter baumannii on Polymyxin B In Vitro2022In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 66, no 1, article id e01789-21Article in journal (Refereed)
    Abstract [en]

    The inoculum effect (i.e., reduction in antimicrobial activity at large starting inoculum) is a phenomenon described for various pathogens. Given that limited data exist regarding inoculum effect of Acinetobacter baumannii, we evaluated killing of A. baumannii by polymyxin B, a last-resort antibiotic, at several starting inocula and developed a pharmacokinetic-pharmacodynamic (PKPD) model to capture this phenomenon. In vitro static time-kill experiments were performed using polymyxin B at concentrations ranging from 0.125 to 128 mg/L against a clinical A. baumannii isolate at four starting inocula from 10(5) to 10(8) CFU/mL. Samples were collected up to 30 h to quantify the viable bacterial burden and were simultaneously modeled in the NONMEM software program. The expression of polymyxin B resistance genes (lpxACD, pmrCAB, and wzc), and genetic modifications were studied by RT-qPCR and DNA sequencing experiments, respectively. The PKPD model included a single homogeneous bacterial population with adaptive resistance. Polymyxin B effect was modeled as a sigmoidal E-max model and the inoculum effect as an increase of polymyxin B EC50 with increasing starting inoculum using a power function. Polymyxin B displayed a reduced activity as the starting inoculum increased: a 20-fold increase of polymyxin B EC50 was observed between the lowest and the highest inoculum. No effects of polymyxin B and inoculum size were observed on the studied genes. The proposed PKPD model successfully described and predicted the pronounced in vitro inoculum effect of A. baumannii on polymyxin B activity. These results should be further validated using other bacteria/antibiotic combinations and in vivo models.

  • 45.
    Al Genaby, Shams
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    En observationsstudie om användbarheten av Janusmed njurfunktion: En kvalitativ studie2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background: In response to the lack of consideration of patient’s kidney function when prescribing drugs, the electronic Clinical Decision Support System (CDSS), Janusmed drugs, and renal function have been developed. This system offers knowledge on prescribing drugs to patients with impaired kidney function. Studies have shown that CDSS has the potential to lower the inappropriate prescription rate for patients with impaired kidney function. However, the general problem that CDSS faces is a low implementation rate because of inadequate usability.

    Aim: The aim was to evaluate the usability of the digital interface Janusmed drugs and renal function and map ways to improve the interface.Method: Think aloud sessions and semi-structured interviews were conducted with eight medical doctors and three clinical pharmacists. Data from the think-aloud sessions were structured through an affinity diagram, also called the KJ-method, to obtain a diagram of how the interface is used and possible improvements of the system. Furthermore, Nielsen’s ten usability heuristics were used to evaluate the usability of the system.

    Results: A total of six violations were found in the system, but they scored low on severity (1-2 points). The affinity diagram obtained showed the following five main themes on ways to improve the system: interface/technical functions, patient data, renal function, self-assessment, and future development.

    Conclusion: Janusmed drugs and renal function is a well-designed and user-friendly CDSS.However, there is still room for further improvements in the design and functionality of the interface that would increase the usability of the system

  • 46.
    Al-Amin, Rasel A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Lars
    Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Center for Molecular Medicine, Department of Medicine (Solna), Science for Life Laboratory, Karolinska Institutet.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Blokzijl, Andries
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hammond, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Haybaeck, Johannes
    Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck; Diagnostic and Research Institute of Pathology, Medical University of Graz.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jenmalm Jensen, Annika
    Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Department of Medical Biochemistry and Biophysics, Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Monitoring drug–target interactions through target engagement-mediated amplification on arrays and in situ2022In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, no 22, p. e129-e129Article in journal (Refereed)
    Abstract [en]

    Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug–target interactions at spatial resolution in protein arrays, cells and in tissues.

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  • 47.
    Al-Amin, Rasel A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for Life Laboratory, SciLifeLab, Science for Life Laboratory, SciLifeLab.
    Johansson, Lars
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Blokzijl, Andries
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Dept. Of Immunology, Genetics and Pathology,.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Target Engagement-Mediated Amplification for Monitoring Drug-Target Interactions in SituManuscript (preprint) (Other academic)
    Abstract [en]

    It is important to determine the localization of drugs or drug candidates at cellular and subcellular resolution in relevant clinical specimens. This is necessary to evaluate drug candidates from early stages of drug development to clinical evaluation of mutations potentially causing resistance to targeted therapy. We describe a technology where oligonucleotide-conjugated drug molecules are used to visualize and measure target engagement in situ via rolling-circle amplification (RCA) of circularized oligonucleotide probes (padlock probes). We established this target engagement-mediated amplification (TEMA) technique using kinase inhibitor precursor compounds, and we applied the assay to investigate target interactions by microscopy in pathology tissue sections and using flow cytometry for blood samples from patients, as well as in commercial arrays including almost half of all human proteins.  In the variant proxTEMAtechnique, in situ proximity ligation assays were performed by combining drug-DNA conjugates with antibody-DNA conjugates to specifically reveal drug binding to particular on- or off-targets in pathological tissues sections. In conclusion, the TEMA methods successfully visualize drug-target interaction by experimental and clinically approved kinase inhibitors in situ and with kinases among a large collection of arrayed proteins. 

  • 48.
    Al-Ani, Abdullah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Investigation of Degarelix aggregation behaviour using All Atom Molecular Dynamics Simulations – effect of counterions2021Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    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.

  • 49. Albertsson, AC
    et al.
    Carlfors, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Sturesson, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Preparation and characterisation of poly(adipic anhydride) microspheres for ocular drug delivery1996In: JOURNAL OF APPLIED POLYMER SCIENCE, Vol. 62, p. 695-Article in journal (Refereed)
  • 50.
    Albitar, Orwa
    et al.
    Univ Sains Malaysia, Sch Pharmaceut Sci, Gelugor 11800, Penang, Malaysia..
    Ghadzi, Siti Maisharah Sheikh
    Univ Sains Malaysia, Sch Pharmaceut Sci, Gelugor 11800, Penang, Malaysia..
    Harun, Sabariah Noor
    Univ Sains Malaysia, Sch Pharmaceut Sci, Gelugor 11800, Penang, Malaysia..
    Ahmad, Siti Nor Aizah
    Minist Hlth Malaysia, Hosp Pulau Pinang, Psychiat Dept, Jalan Residensi, Georgetown 10460, Malaysia..
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pharmacometric modeling of drug adverse effects: an application of mixture models in schizophrenia spectrum disorder patients treated with clozapine2023In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 50, no 1, p. 21-31Article in journal (Refereed)
    Abstract [en]

    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.

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