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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.
    Abbasi, Mina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Translational aspects of unbound brain to plasma concentration ratios2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction:  The unbound brain-to-plasma concentration ratio (Kp,uu,brain) is one of the most important indicators for brain penetration in the area of CNS drug discovery and development. Kp,uu,brain can be calculated by combining the total brain-to-plasma concentration ratio (Kp,brain),  the brain free fraction (fu,brain) and  the plasma free fraction (fu,p).

    Aim:  This study has three purposes, to calculate Kp,uu,brain from publications in humans,  to collect data regarding species differences in Kp,uu,brain and to see whether Kp,uu,brain in humans differs in different  brain regions or not.

    Materials and Methods:  The values of Kp, brain were derived from positron emission tomography (PET), MRS (Magnetic Resonance Spectroscopy), and brain surgery for tumor removal. fu,brain and fu,p were collected from brain homogenate, equilibrium dialysis and ultrafiltration studies.

    Results:  Data on Kp,brain was sparse in the literature. Kp,uu,brain was calculated for sixteen different drugs in humans. According to the calculation, nine of these sixteen compounds were found to be actively influxed into the brain, six were actively effluxed from the BBB and one had a passive diffusion. Depending on the compound, Kp,uu,brain was higher or smaller in humans compared to mice and rats.  Kp,uu,brain for five compounds were calculated for different brain regions. Four compounds had a higher Kp,uu,brain value in almost all other regions than the cerebellum and one had a higher Kp,uu,brain in cerebellum than in the other regions.

    Conclusions:  No definite conclusion on Kp,uu,brain in humans, species differences in Kp,uu,brain  or Kp,uu,brain  in different human brain regions could be reached in this study. In view of the importance of Kp,uu,brain  in CNS drug discovery and development, more studies on Kp,uu,brain in humans and in the other species are required.

  • 5.
    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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  • 6.
    Abdel-Rehim, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Influence of ammonia as carrier gas on separation and detection performance in capillary gas chromatography 1994Doctoral thesis, comprehensive summary (Other academic)
  • 7.
    Abdelwahab, Mahmoud Tareq
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Wasserman, Sean
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Brust, James C. M.
    Albert Einstein Coll Med, Div Gen Internal Med, New York, NY USA.;Albert Einstein Coll Med, Div Infect Dis, New York, NY USA..
    Gandhi, Neel R.
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA.;Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA.;Emory Univ, Emory Sch Med, Dept Med Infect Dis, Atlanta, GA USA..
    Meintjes, Graeme
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Everitt, Daniel
    Global Alliance TB Drug Dev, New York, NY USA..
    Diacon, Andreas
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Dept Med, Cape Town, South Africa..
    Dawson, Rodney
    Univ Cape Town, Lung Inst, Cape Town, South Africa.;Univ Cape Town, Div Pulmonol, Dept Med, Cape Town, South Africa..
    Wiesner, Lubbe
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    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..
    Clofazimine pharmacokinetics in patients with TB: dosing implications2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 11, p. 3269-3277Article in journal (Refereed)
    Abstract [en]

    Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-Linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a Loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a Long elimination half-Life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

  • 8.
    abdi, bahja omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Double-checking advanced drug reconstitution in pediatric care2021Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background 

    An evidence-and experience-based pediatric drug information system, ePed, was developed in Sweden to gather pediatric drug therapy information. Recently a database, Advanced Reconstitution Module (ARM), was designed to detect errors in the reconstitution of high-risk drugs. ARM is integrated with ePed and has a front-end system called ReVal that facilitates communication between the database and DrugLog (an ultraviolet spectrophotometer).  

    Aim 

    The study’s main aim was to ensure correct drug management of high-risk drugs in the neonatal units at Karolinska University Hospital. The study had three objectives; (1) Determination of the prevalence of dilution error for high-risk drugs, (2) Evaluation of the staff experiences with the ARM-system, (3) Investigation of the adsorption of insulin on plastic material.  

    Methods

    Stage 1: Random samples of nine different diluted high-risk drugs used in clinical practice were collected and measured with DrugLog. Stage 2: Recruited participants prepared insulin using ARM. The reconstituted insulin from stage 2 was further studied. 

    Results

    Stage 1: Out of 168 samples, 44.6 % (95 %CI 37.3 %-52.2 %) contained concentrations outside of the acceptable limit (± 10 %). Stage 2: None of the participants found the ARM process difficult, and 34 % of the insulin prepared was outside of the acceptable range. No difference in adsorption (PVC vs. PVC-free lines) was found for insulin.  

    Conclusions

    The first objective of this study was to determine the prevalence of dilution error. With an overall rate of error of 44,6 % the main conclusion that can be drawn from this study is the need for a system that can help minimize this rate of error. The second objective was to evaluate the staff experiences with ARM which was identified to be a simple method according to the participants. More profound studies have to be performed in order to investigate insulins adsorption to plastic which was the studies third objective.  

  • 9.
    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.

  • 10.
    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
  • 11.
    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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  • 12.
    Abdulhameed, Ingi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bedömning av njurfunktionen hos cancerpatinter vid dosering av karboplatin2014Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Vid behandling av ett flertal cancertyper används läkemedlet karboplatin som doseras efter njurfunktionen. Karboplatin utsöndras huvudsakligen via njurarna och elimineringen bestäms framför allt av den glomerulära filtrationshastigheten (GFR). Därför krävs det en noggrann bedömning av njurfunktionen för en korrekt behandling. GFR kan både mätas till exempel med iohexolclearance eller skattas med hjälp av matematiska formler. Det råder en osäkerhet om vilka GFR-metoder som är lämpligast för att skatta njurfunktionen hos cancerpatienter som behandlas med karboplatin.

    Syfte: Att undersöka vilken eller vilka av följande sex GFR skattnings metoder, Cockcroft -Gault med okompenserat kreatinin (CGold), Cockcroft–Gault (CG) med kompenserat kreatinin, cystatin C-GFR, Modification of Diet in Renal Disease Study (MDRD4), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) samt Lund-Malmö formeln (LM-reviderad), som bäst korrelerar till ”gold standard” metoden iohexolclearance, för att bättre kunna dosera karboplatin till cancerpatienter.

    Material och metoder: Femtioåtta cancerpatienter från Radiumhemmet som under 2013 genomfört iohexolclearance innan behandlingsstart med karboplatin inkluderades. GFR hos dessa patienter beräknades med ovanstående formler. Överensstämmelse mellan iohexolclearance och övriga GFR metoder bestämdes med bland annat linjär regression, bias och precision.

    Resultat: CGold och Cystatin C tenderar att underskatta GFR medan MDRD4, CKD-Epi och CG tenderar att överskatta GFR. LM-reviderad överensstämmer med iohexolclearance.

    Konklusion: Lund-Malmö formeln (LM-reviderad) är den metod som bäst korrelerar till ”gold standard” metoden iohexolclearance.

  • 13.
    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.

  • 14. Abdurahman, Samir
    et al.
    Vegvari, Akos
    Youssefi, Masoud
    Levi, Michael
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Andersson, Elin
    Horal, Peter
    Svennerholm, Bo
    Balzarini, Jan
    Vahlne, Anders
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH2), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH2 itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 15. Abela, D
    et al.
    Ritchie, H
    Ababneh, D
    Gavin, C
    Nilsson, Mats F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Niazi, M Khalid Khan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis.
    Carlsson, K
    Webster, WS
    The effect of drugs with ion channel-blocking activity on the early embryonic rat heart2010In: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 89, no 5, p. 429-440Article in journal (Refereed)
    Abstract [en]

    This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the IKr/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or IKr/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

  • 16.
    Abiri, Pojan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Användandet av webbsajten Sil Online – Svenska informationstjänster för läkemedel: En enkät- och intervjustudie2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Sil, Svenska informationstjänster för läkemedel, tillhandahåller kvalitetssäkrad läkemedelsinformation till aktörer inom hälso- och sjukvård. Sil Online (www.silonline.se) möjliggör åtkomsten till informationen i Sil databasen.

    Syfte: Att utvärdera vilka som är användare av Sil Online, i vilket ändamål användningen sker samt vilken information som söks på Sil Online för att skapa underlag för framtidsutveckling av webbsajten.

    Material och metoder: En deskriptiv tvärsnittsstudie bestående av en kvantitativ webbenkätundersökning (tidsperiod: 2015-03-05 till 2015-04-02) och en kvalitativ intervjuerundersökning bland frivilliga respondenter på webbenkäten.

    Resultat: Den största användargruppen bland respondenterna av webbenkäten var farmacevter (67 %), följt av systemutvecklare (16 %) varav majoriteten (43 %) jobbade inom hälso- och sjukvård eller förvaltning och administration inom landsting och kommuner (24 %). Aktuell läkemedelsinformation söktes av majoriteten av användarna (78 %) och mer än hälften (77 %) tyckte att det var lätt att hitta på webbsajten. Intervjurespondenterna saknade information om syftet med Sil Online men tyckte att det var en informativ sajt med unik information om licensläkemedel och listor med landstingens rekommenderade läkemedel. Tydligare instruktioner skulle förbättra användarvänlighet och marknadsföring skulle vidga användarkretsen.

    Konklusion: Sil Online upplevs vara en användarvänlig och informativ webbsajt. Studien visar att det finns potential för utveckling inom presentation och marknadsföring av webbsajten.

  • 17.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, K. Johan
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity2015In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 16, no 7, p. 1068-1077Article in journal (Refereed)
    Abstract [en]

    Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin.

  • 18.
    Aboye, Teshome Leta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Engineering of the Ultra-stable Cystine Knot Framework of Microproteins: Design, Chemical Synthesis and Structural Studies2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ultra-stable cystine knotted microproteins, in which two disulfides and their connecting backbones form a circle that is penetrated by the third disulfide bonds, have attracted high interest due to their resistance to degradation in vitro and potential for the development of peptide drugs. This thesis gives new insights into engineering of that framework of microproteins, including approaches to their chemical synthesis, backbone engineering, structural and biological evaluations.

    Synthetic and oxidative folding approaches for bracelet cyclotides, a family of cyclic cystine knotted microproteins, was developed using a model peptide, cycloviolacin O2. Following assembly of the peptide chain, protected peptide was generated by mild cleavage that was subsequently thioesterified and cyclized in solution. The cyclic peptide was oxidatively folded under optimized conditions containing co-solvent and non-ionic detergent affording native cycloviolacin O2 as a major product. To gain further insights into the heterogeneity, efficiency and kinetics of cyclotides’ oxidative folding, the intermediates that accumulate in oxidative refolding pathways of all cyclotide subfamilies: Möbius, bracelet and the hybrid cyclotides were quantitatively determined under four different folding conditions. The results were used for defining major folding pathways, which indicated that Möbius cyclotides might accumulate heterogeneous folding intermediates with one-, two- and three-disulfides, whereas bracelet tend to accumulate a homogenous intermediate with three-disulfides, depending on the buffer systems used.

    Furthermore, to probe the internal factors contributing to inefficiency of oxidative folding, as well as undesired bioactivities of bracelet cyclotides (e.g., cytotoxic activity), polymer-hybridized cyclotides were designed by replacing non-conserved residues with small isosteric polymers. The designed hybrid analogs in which hybridization involved replacement of loop 3 with isosteric polymers showed improved synthetic and oxidative folding properties. The cytoxicity of a model hybrid designed with replacement of loop 3 and 5 exhibited no cytotoxic activity at concentration of 128-fold relative to that of native peptide. Furthermore, 1D and 2D 1H NMR analysis of this hybrid showed that it had well structured fold.

    List of papers
    1. Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Open this publication in new window or tab >>Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145716 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
    2. Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    Open this publication in new window or tab >>Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    2008 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 1, p. 103-113Article in journal (Refereed) Published
    Abstract [en]

    The cyclic cystine knot motif, as defined by the cyclotide peptide family, is an attractive scaffold for protein engineering. To date, however, the utilisation of this scaffold has been limited by the inability to synthesise members of the most diverse and biologically active subfamily, the bracelet cyclotides. This study describes the synthesis and first direct oxidative folding of a bracelet cyclotide-cycloviolacin O2-and thus provides an efficient method for exploring the most potent cyclic cystine knot peptides. The linear chain of cycloviolacin O2 was assembled by solid-phase Fmoc peptide synthesis and cyclised by thioester-mediated native chemical ligation, and the inherent difficulties of folding bracelet cyclotides were successfully overcome in a single-step reaction. The folding pathway was characterised and was found to include predominating fully oxidised intermediates that slowly converted to the native peptide structure.

    Keywords
    cyclotides, native chemical ligation, peptides, protein folding, synthesis, thioesters
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-98767 (URN)10.1002/cbic.200700357 (DOI)000252292200017 ()18058973 (PubMedID)
    Available from: 2009-03-03 Created: 2009-03-03 Last updated: 2018-01-13Bibliographically approved
    3. An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    Open this publication in new window or tab >>An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    2010 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, no 3, p. 167-176Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are mini-proteins of approximately 30 amino acid residues that have a unique structure consisting of a head-to-tail cyclized backbone and a knotted arrangement of three disulfide bonds. This unique cyclotide structure provides exceptional stability to chemical, enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents. In the current work, we present the first method for microwave assisted Fmoc-SPPS of cyclotides. This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for Fmoc-SPPS of the peptide backbone, the cleavage of the protected peptide and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies-the Mobius kalata B1, the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTI-II. In addition, a "one pot" reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTI-II.

    Keywords
    Cyclotides, Microwave chemistry, Fmoc-SPPS, Circular proteins, Cystine knot, Native chemical ligation
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-134899 (URN)10.1007/s10989-010-9221-0 (DOI)000281682600007 ()
    Available from: 2010-12-02 Created: 2010-12-02 Last updated: 2022-01-28Bibliographically approved
    4. Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Open this publication in new window or tab >>Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Show others...
    2011 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-139359 (URN)10.1089/ars.2010.3112 (DOI)000284572100009 ()20486762 (PubMedID)
    Available from: 2010-12-23 Created: 2010-12-23 Last updated: 2022-01-28Bibliographically approved
    5. Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    Open this publication in new window or tab >>Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145719 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
    Download full text (pdf)
    FULLTEXT01
  • 19.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Roig, Marta Bajona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, p. 77-86Article in journal (Refereed)
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

  • 20.
    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.

  • 21.
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Biopharmaceutical aspects of extended release tablets based on the hydrophilic matrix principle 1997Doctoral thesis, comprehensive summary (Other academic)
  • 22.
    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
  • 23.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia..
    Marklund, Niklas
    Department of Clinical Sciences Lund, Neurosurgery, Skåne University Hospital Lund University, Lund, Sweden .
    Differential DNA methylation of the genes for amyloid precursor protein, tau and neurofilaments in human traumatic brain injury2021In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 38, no 12, p. 1679-1688Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration, e.g. amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM) and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients to iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828 888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain and may have implications for the neurodegenerative disorders associated at long-term with TBI. 

  • 24.
    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
    Download full text (pdf)
    fulltext
  • 25.
    Abualqumssan, Tala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Extemporeformulering till den pediatriska populationen för oral administrering2023Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Sammanfattning 

    Introduktion

    Den pediatriska populationen utesluts ofta från kliniska prövningar av läkemedel. Vilket i sin tur har lett till att marknadsförda läkemedel är avsedda för vuxenbruk, och därför ofta finns i olämpliga läkemedelsformer, doser eller innehållande olämpliga hjälpämne för barn. Detta innebär ett stort behov för mer barnanpassat läkemedel, vilket kan åstadkommas genom extemporetillverkning av läkemedel till barn.  

    Syfte

    Syftet med denna litteraturstudie är att undersöka faktorer som övervägs vid extemporeformulering av flytande läkemedelsformer till barn för oral administrering, samt att redogöra för alternativ till flytande läkemedelsformer till barn. 

    Resultat/Slutsats

    Den vanligaste läkemedelsformen som extemporetillverkas till barn är orala lösningar/suspensioner, som eliminerar problem hos barn såsom sväljningssvårigheter. Orala lösningar/suspensioner innebär dock vissa utmaningar när det gäller behovet av hjälpämne för att erhålla en god, smaklig och stabil beredning, men även dess dosering, som behöver göras med ett administreringshjälpmedel kan vara problematiskt. 

    Läkemedelsformen munsönderfallande filmer (Orodispersible films, ODFs) har visat sig vara en god introduktion till extemporetillverkningen och anses vara särskilt lämpliga för extemporetillverkning till barn. Filmerna är lätt att inta och kommer i avdelade doser anpassade till barnet. 

  • 26. Abu-Bakar, A'edah
    et al.
    Lämsä, Virpi
    Arpiainen, Satu
    Moore, Michael R.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Hakkola, Jukka
    Regulation of CYP2A5 gene by the transcription factor nuclear factor (erythroid-derived 2)-like 22007In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 35, no 5, p. 787-794Article in journal (Refereed)
    Abstract [en]

    We have previously shown that cadmium, a metal that alters cellular redox status, induces CYP2A5 expression in nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2(-/-)) mice but not in the knockout (Nrf2(-/-)) mice. In the present studies, the potential role of Nrf2 in cadmium-mediated regulation of Cyp2a5 gene was investigated in mouse primary hepatocytes. Cadmium chloride (CdCl2) caused a time-dependent induction of the CYP2A5 at mRNA, protein, and activity levels, with a substantial increase observed within 3 h of exposure. Immunoblotting showed cadmium-dependent nuclear accumulation of Nrf2 within 1 h of exposure. Cotransfection of mouse primary hepatocytes with Cyp2a5 promoter-luciferase reporter plasmids and Nrf2 expression plasmid resulted in a 3-fold activation of Cyp2a5 promoter-mediated transcription relative to the control. Deletion analysis of the promoter localized the Nrf2 responsive region to an area from -2656 to -2339 base pair. Computer-based sequence analysis identified two putative stress response elements (StRE) within the region at positions -2514 to -2505 and -2386 to -2377. Chromatin immunoprecipitation and electrophoretic mobility shift assays showed that interaction of the more proximal StRE with Nrf2 was stimulated by CdCl2. Finally, site-directed mutagenesis of the proximal StRE in Cyp2a5 promoter-luciferase reporter plasmids abolished Nrf2 mediated induction. Collectively, the results indicate that Nrf2 activates Cyp2a5 transcription by directly binding to the StRE in the 5'-flanking region of the gene. This acknowledges Cyp2a5 as the first phase I xenobiotic-metabolizing gene identified under the control of the StRE-Nrf2 pathway with a potential role in adaptive response to cellular stress.

  • 27.
    Abulfathi, Ahmed A.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Assawasuwannakit, Piyanan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Donald, Peter R.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa..
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens2020In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 76, no 11, p. 1557-1565Article in journal (Refereed)
    Abstract [en]

    Purpose Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens.

    Methods To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER.

    Results The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for >= 98% of the dosing interval in all the evaluated PASER regimens.

    Conclusion The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.

  • 28.
    Abulfathi, Ahmed A.
    et al.
    Univ Florida, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Orlando, FL 32827 USA.;Univ Maiduguri, Coll Med Sci, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Chaba, Linda A.
    Strathmore Univ, Strathmore Inst Math Sci, Nairobi, Kenya..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Pillai, Goonaseelan C.
    Univ Cape Town, Fac Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Rosenkranz, Bernd
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Fundisa African Acad Med Dev Cape Town, Cape Town, South Africa..
    Pharmacometrics - tools to assure optimal medicine use in low- and middle-income countries: Editorial2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 1034807Article in journal (Other academic)
    Download full text (pdf)
    FULLTEXT01
  • 29.
    Abulfathi, Ahmed A.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Stellenbosch, South Africa.;Univ Maiduguri, Coll Med Sci, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria..
    de Jager, Veronique
    Task Appl Sci, Bellville, South Africa..
    van Brakel, Elana
    Task Appl Sci, Bellville, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Stellenbosch, South Africa..
    Gupte, Nikhil
    Johns Hopkins Univ, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Vanker, Naadira
    Task Appl Sci, Bellville, South Africa..
    Barnes, Grace L.
    Johns Hopkins Univ, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Nuermberger, Eric
    Johns Hopkins Univ, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Dorman, Susan E.
    Med Univ South Carolina, Dept Med, Charleston, SC USA..
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Stellenbosch, South Africa..
    Dooley, Kelly E.
    Johns Hopkins Univ, Div Clin Pharmacol, Dept Med, Ctr TB Res, Baltimore, MD USA.;Johns Hopkins Univ, Div Infect Dis, Dept Med, Ctr TB Res, Baltimore, MD USA..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands..
    The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis2021In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 637618Article in journal (Refereed)
    Abstract [en]

    Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.

    Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.

    Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.

    Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

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  • 30.
    Abulfathi, Ahmed A.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Donald, Peter R.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa..
    Adams, Kim
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance2020In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 86, no 11, p. 2123-2132Article, review/survey (Refereed)
    Abstract [en]

    Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.

  • 31.
    Abulfathi, Ahmed Aliyu
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Decloedt, Eric H.
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa.
    Donald, Peter
    Stellenbosch Univ, Fac Med & Hlth Sci, Paediat & Child Hlth & Desmond Tutu TB Ctr, Cape Town, South Africa.
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis2019In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 58, no 9, p. 1103-1129Article, review/survey (Refereed)
    Abstract [en]

    The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (C-max) > 8.2 mu g/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >= 8 mu g/mL. A higher rifampicin C-max is required for severe forms TB such as TB meningitis, with C-max >= 22 mu g/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC(6)) >= 70 mu g.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C-max/MIC (minimum inhibitory concentration) and AUC/MIC.

  • 32. Abuzooda, Thana
    et al.
    Amini, Ahmad
    Swedish Drug Agency,751 03 Uppsala, Sweden.
    Abdel-Rehim, Mohamed
    Graphite-based microextraction by packed sorbent for online extraction of β-blockers from human plasma samples2015In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 992, p. 86-90Article in journal (Refereed)
    Abstract [en]

    In the present work a new graphitic material (Carbon-XCOS) was used as a sorbent for microextraction by packed sorbent (MEPS). The β-blockers metoprolol and acebutolol in plasma samples were extracted and detected online using Carbon-MEPS syringe and liquid chromatography and tandem mass spectrometry (LC-MS/MS). Factors affecting the MEPS performance such as conditioning, washing and elution solutions were investigated. The validation of the bioanalytical method was performed using human plasma. The standard curve ranged from 10 to 2000nM and the lower limit of quantification (LLOQ) was set to 10nM. The method validation showed good accuracy and precision for the quality control (QC) samples at three concentration levels (30, 800 and 1600nM). The accuracy values of the QC samples were in the range of 86-108% (n=18). The precision values of intra- and inter-day for QC samples ranged from 4.4% to 14.4% (RSD) for the both studied analytes. The coefficient of determination (R(2)) values were ≥0.999 (n=3).

  • 33. Ackermann, Paul
    et al.
    Spetea, Mariana
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ploj, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ahmed, Mahmood
    Kreicbergs, Andris
    An opioid system in connective tissue: A study of Achilles tendon in the rat2001In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 49, no 11, p. 1387-1395Article in journal (Refereed)
    Abstract [en]

    The occurrence of endogenous opioids and their receptors in rat achilles tendon was analyzed by immunohistochemistry (IHC), radioimmunoassay (RIA), and in vitro binding assays. The investigation focused on four enkephalins, dynorphin B, and nociceptin/orphanin FQ. Nerve fibers immunoreactive to all enkephalins (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Gly-Lys, Met-enkephalin-Arg-Phe) were consistently found in the loose connective tissue and the paratenon, whereas dynorphin B and nociceptin/orphanin FQ could not be detected. The majority of enkephalin-positive nerve fibers exhibited varicosities predominantly seen in blood vessel walls. Measurable levels of Met-enkephalin-Arg-Phe and nociceptin/orphanin FQ were found in tendon tissue using RIA, whereas dynorphin B could not be detected. In addition to the endogenous opioids identified, delta -opioid receptors on nerve fibers were also detected by IHC. Binding assays to characterize the opioid binding sites showed that they were specific and saturable for [H-3]-naloxone (K-d 7.01 +/- 0.98 nM; B-max 23.52 +/- 2.23 fmol/mg protein). Our study demonstrates the occurrence of an opioid system in rat achilles tendon, which may be assumed to be present also in other connective tissues of the locomotor apparatus. This system may prove to be a useful target for pharmacological therapy in painful and inflammatory conditions by new drugs acting selectively in the periphery.

  • 34.
    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.

  • 35.
    Adem, Abdu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Characterization of muscarinic and nicotinic receptors in neural and non-neural tissue: changes in Alzheimer's disease 1987Doctoral thesis, comprehensive summary (Other academic)
  • 36.
    Adeyemi, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(0)-Catalyzed Synthesis of Spirocycles and Supercritical Chemistry using a Resistively Heated Flow Reactor2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This doctoral thesis focusses on an effective and selective approach to the synthesis of spirocycles using palladium(0)-catalyzed Mizoroki-Heck reactions. In addition, selective and efficient chemistry was highlighted by the design and evaluation of a novel resistively heated system for continuous flow (CF) synthesis for high-temperature and high-pressure applications.

    Paper I described the design and evaluation of a novel resistively heated CF system. The design of a low-cost, simple, robust, and effective CF system involving a resistively heated steel reactor capable of delivering 400 °C and 200 bar was reported. The reactor was evaluated with esterification, transesterification and direct carboxylic acid to nitrile conversions using supercritical ethanol, methanol and acetonitrile respectively. Diels-Alder reactions under neat conditions were also carried out at high temperature and pressure.

    Paper II reported the synthesis of spirooxindoles by a selective application of the palladium(0)-catalyzed Mizoroki-Heck spirocyclization. The precursors for the reaction were synthesized by coupling 2-iodoanilines with esters derived from enantiomerically pure (+)-Vince lactam decorated with the bulky, directing 2,5-dimethylpyrrole protecting group. Ten different spirooxindoles were reported with good yields and high regio- and stereoselectivity. Functionalization of a synthesized spirooxindole was done by a palladium(0)-catalyzed alkoxycarbonylation, followed by selective deprotections.

    In Paper III, ether precursors were synthesized from (+)-Vince lactam, via a Mitsunobu reaction with the corresponding iodophenols. The precursors were later subjected to conditions for intramolecular Mizoroki-Heck reaction. Overall, 12 spiroethers were synthesized in useable yields, regioselectivity up to 98% and with excellent diastereoselectivity (d.e.>98%). Further functionalization to mono-protected rigidified amino acids was also demonstrated.

    List of papers
    1. Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
    Open this publication in new window or tab >>Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
    Show others...
    2017 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, p. 947-955Article in journal (Refereed) Published
    Abstract [en]

    A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

    Place, publisher, year, edition, pages
    AMER CHEMICAL SOC, 2017
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-333407 (URN)10.1021/acs.oprd.7b00063 (DOI)000406356200003 ()
    Funder
    EU, FP7, Seventh Framework Programme, 607517
    Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2020-01-16Bibliographically approved
    2. Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides
    Open this publication in new window or tab >>Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki-Heck Coupling of Aryl Iodides
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    2019 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, no 1, p. 82-88Article in journal, Letter (Refereed) Published
    Abstract [en]

    A method for highly regio- and stereoselective intramolecular Mizoroki-Heck 5- exo cyclization of aryl iodides to the corresponding spirooxindoles has been developed. Electron-rich and electron-deficient aryl iodide precursors were selectively ring-closed with high stereoselectivity and good yields. The double-bond position in the cyclopentene ring was controlled by careful choice of reaction conditions. These rare spiro compounds were further functionalized to rigidified unnatural amino acid derivatives by a subsequent gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O - and N -deprotections.

    Place, publisher, year, edition, pages
    GEORG THIEME VERLAG KG, 2019
    Keywords
    spirooxindoles, Mizoroki-Heck, cyclization, carbonylation
    National Category
    Medicinal Chemistry Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-372880 (URN)10.1055/s-0037-1611360 (DOI)000453250700013 ()
    Funder
    EU, FP7, Seventh Framework Programme, 607517
    Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2020-01-16Bibliographically approved
    3. Regio- and Stereo-Selective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via Intramolecular Mizoroki-Heck Reaction
    Open this publication in new window or tab >>Regio- and Stereo-Selective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via Intramolecular Mizoroki-Heck Reaction
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Palladium(0)-catalyzed intramolecular annulation of twelve 1,3-disubstituted cyclopentenes, derived from (+)-vince lactam, resulted in 5-exo cyclizations, furnishing a series of 2,5-dimethyl-1-((3R,4'S)-2H-spiro[benzofuran-3,1'-cyclopentan]-2'-en-4'-yl)-1H-pyrroles in excellent diastereoselectivities and useful isolated yields. The double bond migration process, following the arylpalladium insertion, was controlled by fine-tuning of the reaction system, providing regioselectivities of up to 98:2. The selective Mizoroki-Heck reaction was used as the key transformation for preparing two new spirocyclic monoprotected amino acids as single diastereoisomers.

    National Category
    Organic Chemistry Pharmaceutical Sciences
    Research subject
    Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-402335 (URN)
    Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-01-24
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  • 37. Adeyemi, Ahmed
    Regio- and Stereo-Selective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via Intramolecular Mizoroki-Heck ReactionManuscript (preprint) (Other academic)
    Abstract [en]

    Palladium(0)-catalyzed intramolecular annulation of twelve 1,3-disubstituted cyclopentenes, derived from (+)-vince lactam, resulted in 5-exo cyclizations, furnishing a series of 2,5-dimethyl-1-((3R,4'S)-2H-spiro[benzofuran-3,1'-cyclopentan]-2'-en-4'-yl)-1H-pyrroles in excellent diastereoselectivities and useful isolated yields. The double bond migration process, following the arylpalladium insertion, was controlled by fine-tuning of the reaction system, providing regioselectivities of up to 98:2. The selective Mizoroki-Heck reaction was used as the key transformation for preparing two new spirocyclic monoprotected amino acids as single diastereoisomers.

  • 38.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Regio- and Stereoselective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via an Intramolecular Mizoroki-Heck Reaction2020In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 85, no 12, p. 7648-7657Article in journal (Refereed)
    Abstract [en]

    The palladium(0)-catalyzed intramolecular annulation of 12 1,3-disubstituted cyclopentenes, derived from (+)-vincelactam, resulted in 5-exo cyclizations which furnished a series of 2,5-dimethyl-14(3R,4'S)-2H-spiro[benzofuran-3,1'-cyclopentan]2'-en-4'-yl)-1H-pyrroles in excellent diastereoselectivities and useful isolated yields. The double bond migration process that followed the arylpalladium insertion was controlled by a fine-tuning of the reaction system, which provided regioselectivities of up to 98:2. The selective Mizoroki-Heck reaction was used as the key transformation for preparing two new spirocyclic monoprotected amino acids as single stereoisomers.

  • 39.
    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. 

  • 40.
    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.

  • 41. Adomas, Aleksandra
    et al.
    Eklund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johansson, Martin
    Asiegbu, Frederick O.
    Identification and analysis of differentially expressed cDNAs during nonself-competitive interaction between Phlebiopsis gigantea and Heterobasidion parviporum2006In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 57, no 1, p. 26-39Article in journal (Refereed)
    Abstract [en]

    The molecular factors regulating interspecific interaction between the saprotrophic biocontrol fungus Phlebiopsis gigantea and the conifer pathogen Heterobasidion parviporum were investigated. We constructed cDNA libraries and used expressed sequence tag analysis for the identification and characterization of genes expressed during the self and nonself-hyphal interaction. cDNA clones from either the pathogen or biocontrol agent were arrayed on nylon membrane filters and differentially screened with cDNA probes made from mycelia forming the barrage zone during nonself-interactions, mycelia growing outside the barrage zones or monocultures. BlastX analysis of the differentially expressed clones led to the identification of genes with diverse functions, including those with potential as virulence factors, such as hydrophobins. Because of the high sequence conservation (r2 = 0.81) between P. gigantea and H. parviporum, a selected number of genes from either fungus were used to monitor the expression profile under varying interaction conditions by virtual northern blot. The results are discussed with respect to the potential role of the induced genes during the nonself-competitive interaction for space and nutrients between P. gigantea and H. parviporum.

  • 42.
    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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    fulltext
  • 43.
    Ahlberg, Ernst
    et al.
    AstraZeneca Innovat Med & Early Dev, Drug Safety & Metab, Molndal, Sweden..
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hasselgren, Catrin
    Univ New Mexico, Internal Med, Albuquerque, NM 87131 USA..
    Carlsson, Lars
    AstraZeneca Innovat Med & Early Dev, Drug Safety & Metab, Molndal, Sweden..
    Interpretation of Conformal Prediction Classification Models2015In: STATISTICAL LEARNING AND DATA SCIENCES, 2015, p. 323-334Conference paper (Refereed)
    Abstract [en]

    We present a method for interpretation of conformal prediction models. The discrete gradient of the largest p-value is calculated with respect to object space. A criterion is applied to identify the most important component of the gradient and the corresponding part of the object is visualized. The method is exemplified with data from drug discovery relating chemical compounds to mutagenicity. Furthermore, a comparison is made to already established important subgraphs with respect to mutagenicity and this initial assessment shows very useful results with respect to interpretation of a conformal predictor.

  • 44.
    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
  • 45.
    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.

  • 46.
    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.

  • 47.
    Ahlneck, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Some studies on the effect of moisture sorption on stability, compatibility and compaction properties of drugs and excipients in the solid state 1988Doctoral thesis, comprehensive summary (Other academic)
  • 48.
    Ahlsén, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Hultén, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Shuman, Cynthia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Poliakov, Anton
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lindgren, Maria T.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Resistance profiles of cyclic and linear inhibitors of HIV-1 protease2002In: Antiviral Chemistry & Chemotherapy, ISSN 0956-3202, E-ISSN 2040-2066, Vol. 13, no 1, p. 27-37Article in journal (Refereed)
    Abstract [en]

    Resistance to anti-HIV protease drugs is a major problem in the design of AIDS drugs with long-term efficacy. To identify structural features associated with a certain resistance profile, the inhibitory properties of a series of symmetric and asymmetric cyclic sulfamide, cyclic urea and linear transition-state analogue inhibitors of HIV-1 protease were investigated using wild-type and mutant enzyme. To allow a detailed structure-inhibition analysis, enzyme with single, double, triple and quadruple combinations of G48V, V82A, 184V and L90M substitutions was used. Kinetic analysis of the mutants revealed that catalytic efficiency was 1-30% of that for the wild-type enzyme, a consequence of reduced kcat in all cases and an increased KM for all mutants except for the G48V enzyme. The overall structure-inhibitory profiles of the cyclic compounds were similar, and the inhibition of the V82A, 184V and G48V/L90M mutants were less efficient than of the wild-type enzyme. The greatest increase in Ki was generally observed for the 184V mutant and least for the G48V/L90M mutant, and additional combinations of mutations did not result in improved inhibition profiles for the cyclic compounds. An extended analysis of additional mutants, and including a set of linear compounds, showed that the profile was unique for each compound, and did not reveal any general structural features associated with a certain inhibition profile. The effects of structural modifications in the inhibitors, or of mutations, were not additive and they differed depending on their context. The results demonstrate the difficulties in predicting resistance, even for closely related compounds, and designing compounds with improved resistance profiles.

  • 49. Ahmed, A. Ahmed
    et al.
    El-Seedi, Hesham R.
    Mahmoud, Ahmed A.
    El-Douski, Abd El-Aziz A.
    Zeid, Ibrahim F.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Eudesmane derivatives from Laggera crispata and Pluchea carolonesis1998In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 49, no 8, p. 2421-2424Article in journal (Refereed)
    Abstract [en]

    Investigation of the aerial parts of Laggera crispata and Pluchea carolonesis afforded in addition to several known compounds, three new eudesmane derivatives, 3β,4α-dihydroxy-7-epi-eudesm-11(13)-ene, 3α-(2′,3′-dihydroxy-2′-methylbutanoyl)-4,11-dihydroxy-6,7-dehydroeudesman-8-one and 3α-(3′-chloro-2′-hydroxy-2′-methylbutanoyl)cuauhtemone. The structures were elucidated by spectroscopic methods

  • 50. Ahmed, Aisha S.
    et al.
    Li, Jian
    Ahmed, Mahmood
    Hua, Long
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ossipov, Michael H.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stark, André
    Attenuation of Pain and Inflammation in Adjuvant-Induced Arthritis by the Proteasome Inhibitor MG1322010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 7, p. 2160-2169Article in journal (Refereed)
    Abstract [en]

    Objective. In rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-kappa B, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis. Methods. Arthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-kappa B DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-kappa B subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin generelated peptide (CGRP) were detected by immunohistochemistry. Results. Arthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-kappa B/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132. Conclusion. In arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-kappa B activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA.

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