uu.seUppsala University Publications
Change search
Refine search result
1234567 1 - 50 of 2207
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the 'Create feeds' function.
  • 1.
    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.

  • 2.
    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)
  • 3.
    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.

  • 4. 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.

  • 5. 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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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: 2018-01-12Bibliographically 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: 2018-01-12Bibliographically 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
  • 9.
    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.

  • 10.
    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)
  • 11. 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.

  • 12. 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).

  • 13. 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.

  • 14.
    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.

  • 15.
    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)
  • 16.
    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.

  • 17. 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.

  • 18.
    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.

  • 19.
    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: 2018-01-13Bibliographically 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: 2017-12-14Bibliographically 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: 2018-01-13Bibliographically approved
  • 20.
    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.

  • 21.
    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.

  • 22.
    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)
  • 23.
    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.

  • 24. 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

  • 25. 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.

  • 26. Ahn, Jae Eun
    et al.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dunne, Adrian
    Ludden, Thomas M.
    Likelihood based approaches to handling data below the quantification limit using NONMEM VI2008In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 4, p. 401-421Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To evaluate the likelihood-based methods for handling data below the quantification limit (BQL) using new features in NONMEM VI. METHODS: A two-compartment pharmacokinetic model with first-order absorption was chosen for investigation. Methods evaluated were: discarding BQL observations (M1), discarding BQL observations but adjusting the likelihood for the remaining data (M2), maximizing the likelihood for the data above the limit of quantification (LOQ) and treating BQL data as censored (M3), and like M3 but conditioning on the observation being greater than zero (M4). These four methods were compared using data simulated with a proportional error model. M2, M3, and M4 were also compared using data simulated from a positively truncated normal distribution. Successful terminations and bias and precision of parameter estimates were assessed. RESULTS: For the data simulated with a proportional error model, the overall performance was best for M3 followed by M2 and M1. M3 and M4 resulted in similar estimates in analyses without log transformation. For data simulated with the truncated normal distribution, M4 performed better than M3. CONCLUSIONS: Analyses that maximized the likelihood of the data above the LOQ and treated BQL data as censored provided the most accurate and precise parameter estimates.

  • 27.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Axén, N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A miniaturized in vitro release method for investigating drug-release mechanisms2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, no 1-2, p. 339-349Article in journal (Refereed)
    Abstract [en]

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

  • 28.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, p. 3387-3398Article in journal (Refereed)
    Abstract [en]

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

  • 29.
    Ahnfelt, Nils-Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Gas chromatographic analysis of amines, aminophenols and aminobutyric acids: studies on the derivatization with chloroformate esters1982Doctoral thesis, comprehensive summary (Other academic)
  • 30.
    Akbari Kenari, Sepideh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The role of serotonin and dopamine signalling within the prefrontal cortex and striatum in cognitive function in rats2012Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
  • 31.
    Akcan, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Smärtstillande läkemedelsbehandling hosäldre i Uppsala län - en retrospektiv studie2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Hos äldre är smärta relativt vanligt då det med ökad ålder uppkommerproblem i muskler, leder, senor och skelett, t.ex. artros, osteoporos och sarkopeni.Socialstyrelsen utformade 2004 en mall för god läkemedelsterapi hos äldre, s.k.kvalitetsindikatorer. T.ex. får paracetamol inte överstiga en dygnsdos på 4 g/dygn ochNSAID bör endast användas vid inflammatorisk smärta. När lätta analgetika inte hjälperrekommenderas behandling med starka opioider direkt utan att först använda lättaopioider lätta opioider då dessa anses olämpliga för äldre. Vid perifer neuropatisksmärta rekommenderas i första hand TCA (amitriptylin, nortriptylin) eller gabapentin.Syfte: Det övergripande syftet är att värdera kvaliteten i äldres smärtstillandeläkemedelsbehandling genom att relatera den till rekommenderad behandling för att ökakunskapen om hur behandling med smärtstillande läkemedel ser ut inom äldrevårdenidag. Material och metoder: Läkemedelslistor från 434 patienter från olikaäldreboenden i Uppsala län inkluderas i studien. Insamlade, avidentifierade data fördesin i Excel med information som student-ID, patient-ID, ålder, kön, substansnamn,stående dos, vidbehovsdos och stående + vidbehovsdos. Resultat: Gruppen bestod av299 kvinnor och 135 män med medelåldern 85,4 år. Totalt förskrevs 485 smärtstillandeläkemedel till de 434 patienterna. 75.8 % patienter förskrevs paracetamol, 27,2 %opioider, 3,45 % NSAID, 0,92 % amitriptylin respektive 1,61 % gabapentin.Rekommenderad dygnsdos av paracetamol överskreds hos 13 patienter, av diklofenakhos en patient medan 33 patienter inte hade maximal dygnsdos angiven. Förskrivning avett analgetikum var vanligast och förekom hos 179 patienter. Två analgetika förskrevstill 119 patienter medan två, en man och en kvinna, förskrevs 5 analgetika vardera.Totalt 94 personer, 21,4 %, använde inga smärtstillande läkemedel alls. Konklusion:Studien visar att smärtstillande läkemedelsbehandling hos äldre i Uppsala län inteskiljer sig markant från studier gjorda i övriga Sverige och Europa. Dock var det någrasom, enligt Socialstyrelsen kvalitetsindikatorer, överskred dygnsdosen och stod påläkemedel som anses vara olämpliga för äldre, vilket visar att det fortfarande finnsproblem med äldres läkemedelsterapi.

  • 32. Akhtar, Malik N.
    et al.
    Southey, Bruce R.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sweedler, Jonathan V.
    Rodriguez-Zas, Sandra L.
    Identification of best indicators of peptide-spectrum match using a permutation resampling approach2014In: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 12, no 5, p. 1440001-Article in journal (Refereed)
    Abstract [en]

    Various indicators of observed-theoretical spectrum matches were compared and the resulting statistical significance was characterized using permutation resampling. Novel decoy databases built by resampling the terminal positions of peptide sequences were evaluated to identify the conditions for accurate computation of peptide match significance levels. The methodology was tested on real and manually curated tandem mass spectra from peptides across a wide range of sizes. Spectra match indicators from complementary database search programs were pro filed and optimal indicators were identified. The combination of the optimal indicator and permuted decoy databases improved the calculation of the peptide match significance compared to the approaches currently implemented in the database search programs that rely on distributional assumptions. Permutation tests using p-values obtained from software-dependent matching scores and E-values outperformed permutation tests using all other indicators. The higher overlap in matches between the database search programs when using end permutation compared to existing approaches con firmed the superiority of the end permutation method to identify peptides. The combination of effective match indicators and the end permutation method is recommended for accurate detection of peptides.

  • 33.
    Akkawi, Ranaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eksborg, Staffan
    Andersson, Asa
    Lundeberg, Stefan
    Bartocci, Marco
    Effect of oral naloxone hydrochloride on gastrointestinal transit in premature infants treated with morphine2009In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 98, no 3, p. 442-447Article in journal (Refereed)
    Abstract [en]

    Background: Opioids are common drugs for pain treatment in preterm newborn infants, in spite of several adverse effects. Constipation is a frequent problem when opioids are used in both adults and neonates. Although several studies indicate that the oral administration of naloxone hydrochloride (NH) improves intestinal motility during opioid therapy, there is still a lack of evidence in newborns. Aim: The aim of this study was to assess the efficacy of NH against reduced intestinal motility during opioid treatment. Methods: A retrospective cohort study was performed. We analysed the medical records of fifteen infants (Group 1) treated with continuous morphine (MO) infusion and fourteen infants (Group 2) treated with both oral NH (3 mu g/kg 4 times daily) and MO. Results: There was no statistically significant difference in the total MO dose. Infants treated both with NH and MO had a tendency to improve their mean stool frequency/day. A statistically significant improvement was observed in the mean total food intake (mL/kg/day) of the infants treated with NH (p = 0.014). No difference in the mean food retention between the two groups was observed. Conclusion: Orally administrated NH seems to improve intestinal motility resulting in increased food intake/day and improved stool frequency/day in premature newborn infants treated with MO. Further studies are needed to corroborate these findings.

  • 34.
    Al Haj, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of Dehydration and Blockade of the Renin-Angiotensin System in the One-humped Camel (Camelus dromedarius)2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The one-humped or the dromedarian camel is a pseudo-ruminant mammal, well adapted to the hot and dry climates of the desert. Its ability to withstand torrid heat and extreme desiccation is of paramount importance to its survival. The studies presented in this thesis were designed to investigate and document the effect of dehydration in the presence or absence of angiotensin II (Ang II) AT1 receptor blocker (losartan) on blood constituents, electrolytes, hormones, neurotransmitters as well as liver and kidney enzymes in a subset of dehydrated camels and to compare them with hydrated camels. Additionally, we studied the response of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) and revealed for the first time the cardiac storage form of BNP in the camel heart. Dehydration induced significant increments in packed cell volume (PCV), white blood cells (WBC), gamma glutamyl-transferase (GGT), serum sodium, creatinine and urea levels, and a doubling in plasma cortisol and arginine vasopressin (AVP) levels. At the same time dehydration caused significant decrease in body weights, plasma insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3), and a 50% decrement in ANP and BNP levels. Moreover, dehydration with and without losartan resulted in significant changes in stress hormones and anti-oxidants in plasma, liver and kidney homogenates. Losartan on one hand enhanced the effect of dehydration resulting in significant increases in sodium, creatinine and urea levels. In addition losartan raised the  binding affinity of Ang II AT2 receptors in the small intestine with 8-fold and with 16-fold for liver AT1 receptors, indicating that Ang II AT1 and AT2 receptor binding sites were present in camel's small intestine while only AT1 receptor binding sites were found in the camel liver. One the other hand losartan resulted in significant decrease in body weights impaired the rise in anti-diuretic hormone and reduced aldosterone level. Finally, we showed that the proBNP is the storage form of BNP in the camel heart.

    List of papers
    1. Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
    Open this publication in new window or tab >>Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
    Show others...
    2011 (English)In: Journal of Medical Sciences, ISSN 1996-3262, E-ISSN 1996-3270, Vol. 4, no 2, p. 73-78Article in journal (Refereed) Published
    Abstract [en]

    Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels.

    Methods:Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group(n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5mg/Kg daily by intravenous injection during 20 days of dehydration.  

    Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period ofwater restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls.

    Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

    Keywords
    Blood, camel, dehydration, losartan, and serum
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-207413 (URN)10.2174/1996327001104020073 (DOI)
    Available from: 2013-09-13 Created: 2013-09-13 Last updated: 2018-01-11Bibliographically approved
    2. Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Open this publication in new window or tab >>Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Show others...
    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e37299-Article in journal (Refereed) Published
    Abstract [en]

    Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-177622 (URN)10.1371/journal.pone.0037299 (DOI)000305343500092 ()
    Available from: 2012-07-18 Created: 2012-07-17 Last updated: 2017-12-07Bibliographically approved
    3. Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
    Open this publication in new window or tab >>Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
    Show others...
    2012 (English)In: Comparative Clinical Pathology, ISSN 1618-5641, E-ISSN 1618-565X, Vol. 21, no 6, p. 1745-1749Article in journal (Refereed) Published
    Abstract [en]

    In the present study, the effect of 20 days of dehydration in the presence or absence of losartan (angiotensin II AT1 receptor antagonist) on insulin-like growth factor-1(IGF-1) and insulin-like growth factor-binding protein-3(IGFBP-3) in plasma of the one-humped camel was studied. Eighteen male camels, 3-4 years of age, were divided into three equal groups: control, dehydrated, and dehydrated-losartan-treated groups. The control camels were given food and water ad libitum. The two dehydrated groups underwent 20 days of water deprivation but were given food ad libitum. The dehydrated-losartan-treated camels were given losartan injection (Merck, USA), intravenously at a dose of 5 mg/kg body weight daily for 20 days. Our results demonstrated a progressive decrease in the circulating levels of IGF-1 and IGFBP-3 in the dehydrated and dehydrated-losartan-treated animals across dehydration compared to their basal levels and time-matched control. On day 5 of dehydration, the IGF-1 level in the losartan-treated group showed a decrease of 60 % and the dehydrated group showed 45 % decrease from their baseline levels and time-matched control. On day 10 the decrease in the losartan-treated animals reached 74 % and for the dehydrated was 62 %. On day 20 the decrease in the losartan-treated was 89 % and for the dehydrated reached 80 % from their baseline levels and time-matched control. Dehydration in the presence or absence of losartan caused a decrease in the circulating level of IGFBP-3. The decrement reached 26 % on day 10 and 20 for the treated camels, while the decrease for the dehydrated was 22 % on day 10 of dehydration and reached 29 % on day 20 compared to their baseline levels and time-matched control. In conclusion, dehydration alone, or in presence of Angiotensin II AT1 receptor blocker caused significant decrease in the circulating levels of IGF-1 and IGFBP-3 compared to their basal values and to time-matched controls. Losartan enhanced the effect of dehydration mainly in the early phase of dehydration for both parameters; albeit, no significant differences between the two dehydrated groups was observed. Finally, these findings suggest an essential role of IGF-1and IGFBP-3 in the dehydration state of these dromedarian camels.

    Keywords
    Camel, Dehydration, IGF-1, IGFBP-3, Losartan
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-193751 (URN)10.1007/s00580-012-1562-y (DOI)
    Available from: 2013-02-06 Created: 2013-02-06 Last updated: 2017-12-06Bibliographically approved
    4. ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Open this publication in new window or tab >>ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e57806-Article in journal (Refereed) Published
    Abstract [en]

    The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-200116 (URN)10.1371/journal.pone.0057806 (DOI)000316849200019 ()
    Available from: 2013-05-21 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
    5. Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
    Open this publication in new window or tab >>Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
    Show others...
    2013 (English)In: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, p. 232-Article in journal (Refereed) Published
    Abstract [en]

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

    Keywords
    Camel, Catecholamine, Cortisol, dehydration, Glutathione and Malondialdehyde
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-207417 (URN)10.1186/1746-6148-9-232 (DOI)000329620900001 ()
    Available from: 2013-09-13 Created: 2013-09-13 Last updated: 2018-01-11Bibliographically approved
  • 35.
    Al Haj, Mahmoud
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. United Arab Emirates University.
    Kazzam, Elsadig
    United Arab Emirates University.
    Nagelkerke, Nicolas
    United Arab Emirates University.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nicholls, Gary M.
    Otago University, Christchurch.
    Adem, Abdu
    United Arab Emirates University.
    Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel2011In: Journal of Medical Sciences, ISSN 1996-3262, E-ISSN 1996-3270, Vol. 4, no 2, p. 73-78Article in journal (Refereed)
    Abstract [en]

    Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels.

    Methods:Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group(n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5mg/Kg daily by intravenous injection during 20 days of dehydration.  

    Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period ofwater restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls.

    Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

  • 36.
    Al-Ani, Nadhim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    An experimental study of the complexation between Cu(2+) and some a-amino acids with emphasis on stereoselective effects1984Doctoral thesis, comprehensive summary (Other academic)
  • 37.
    Alassaad, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Improving the Quality and Safety of Drug Use in Hospitalized Elderly: Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

    List of papers
    1. Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial
    Open this publication in new window or tab >>Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e62401-Article in journal (Refereed) Published
    Abstract [en]

    Background: Appropriateness of prescribing can be assessed by various measures and screening instruments. The aims of this study were to investigate the effects of pharmacists' interventions on appropriateness of prescribing in elderly patients, and to explore the relationship between these results and hospital care utilization during a 12-month follow-up period. Methods: The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalization was investigated, was used. The criteria from the instruments MAI, STOPP and START were applied retrospectively to the 368 study patients (intervention group (I) n = 182, control group (C) n = 186). The assessments were done on admission and at discharge to detect differences over time and between the groups. Hospital care consumption was recorded and the association between scores for appropriateness, and hospitalization was analysed. Results: The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for I but not for C (1.42 to 0.93 vs. 1.46 to 1.66 respectively, p<0.01). The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for I but not for C (0.36 to 0.09 vs. 0.42 to 0.45 respectively, p<0.001). The summated score for MAI was reduced for I but not for C (8.5 to 5.0 and 8.7 to 10.0 respectively, p<0.001). There was a positive association between scores for MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively). No association was detected between the scores of the tools and total re-visits to hospital. Conclusion: The interventions significantly improved the appropriateness of prescribing for patients in the intervention group as evaluated by the instruments MAI, STOPP and START. High scores in MAI and STOPP were associated with a higher number of drug-related readmissions.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-203295 (URN)10.1371/journal.pone.0062401 (DOI)000319107900008 ()
    Available from: 2013-07-08 Created: 2013-07-08 Last updated: 2017-12-06Bibliographically approved
    2. The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing
    Open this publication in new window or tab >>The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing
    Show others...
    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e111797-Article in journal (Refereed) Published
    Abstract [en]

    Background: Clinical pharmacist interventions have been shown to have positive effect on occurrence of drug-related issues as well as on clinical outcomes. However, evidence about which patients benefiting most from the interventions is limited. We aimed to explore whether pharmacist intervention is equally effective in preventing emergency department (ED) visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing. Methods: Patient and outcome data from a randomized controlled trial exploring the clinical effects of a ward-based pharmacist intervention in patients, 80 years and older, were used. The patients were divided into subgroups according to the number of prescribed drugs (< 5 or >= 5 drugs) and the level of inappropriate prescribing [using the Screening Tool Of Older People's potentially inappropriate Prescriptions (STOPP) and the Screening Tool to Alert doctors to Right Treatment (START) with a score of >= 2 (STOPP) and >= 1 (START) as cutoff points]. The effect of the intervention on the number of times the different subgroups visited the ED was analyzed. Results: The pharmacist intervention was more effective with respect to the number of subsequent ED visits in patients taking < 5 drugs on admission than in those taking >= 5 drugs. The rate ratio (RR) for a subsequent ED visit was 0.22 [95% confidence interval (CI) 0.09-0.52] for,5 drugs and 0.70 (95% CI 0.47-1.04) for >= 5 drugs (p = 0.02 for the interaction). The effect of intervention did not differ between patients with high or low STOPP or START scores. Conclusion: In this exploratory study, the pharmacist intervention appeared to be more effective in preventing visits to the ED for patients who were taking fewer drugs before the intervention. Our analysis of STOPP and START scores indicated that the level of inappropriate prescribing on admission had no effect on the outcomes of intervention with respect to ED visits.

    Keywords
    clinical pharmacy, medication review, inappropriate prescribing, polypharmacy, geriatrics
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-234485 (URN)10.1371/journal.pone.0111797 (DOI)000345558100122 ()25364817 (PubMedID)
    Available from: 2014-10-20 Created: 2014-10-20 Last updated: 2017-12-05Bibliographically approved
    3. A tool for prediction of risk of rehospitalization and mortality in hospitalized elderly
    Open this publication in new window or tab >>A tool for prediction of risk of rehospitalization and mortality in hospitalized elderly
    Show others...
    (English)Article in journal (Refereed) Submitted
    Abstract [en]

    Importance: Older patients with multiple co-morbidities and multi-drug use are at high risk of revisits to hospital and mortality, which poses an increasing health economic burden.

    Objective: To construct and internally validate a risk score, the “80+ score”, for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person’s Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI).

    Design: Secondary use of data from a randomized controlled trial investigating effects of a comprehensive pharmacist intervention, conducted in 2005-2006.

    Setting: Two acute internal medicine wards at Uppsala University hospital.

    Participants: Data from 368 patients, 80 years and older, admitted to one of the study wards.

    Main outcomes and measures: Time to rehospitalization or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk-estimation was constructed.  The score was internally validated, and the discriminatory ability of the new score and of STOPP, START and MAI was assessed using C-statistics.

    Results: Seven variables were selected for the 80+ score. Impaired renal function, pulmonary disease (chronic obstructive pulmonary disease [COPD or asthma]), malignant disease (past or present), living in nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease was associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+ score), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI).

    Conclusion and Relevance: We developed and internally validated a score for prediction of risk of rehospitalization and mortality in hospitalized older people. The score discriminated risk considerably better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions. 

    Keywords
    Geriatrics, drugs, risk-estimation, polypharmacy, pharmacotherapy
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-234487 (URN)
    Available from: 2014-10-20 Created: 2014-10-20 Last updated: 2015-02-03Bibliographically approved
    4. Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study
    Open this publication in new window or tab >>Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study
    Show others...
    2013 (English)In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, no 1, p. 185-191Article in journal (Refereed) Published
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

    Keywords
    medication error, medication reconciliation, multi-dose dispensed medications, patient safety, prescription error, transition of care
    National Category
    Social and Clinical Pharmacy
    Research subject
    Pharmaceutical Science; Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-167137 (URN)10.1111/j.1365-2753.2011.01798.x (DOI)000314114400026 ()
    Available from: 2012-01-22 Created: 2012-01-22 Last updated: 2018-01-12
  • 38.
    Albin, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    En klinisk farmaceuts arbete i primärvården – Uppföljning av läkemedelsgenomgångar2018Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

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

  • 39.
    al-breihi, ayat
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Development of an analytical method for the cyclotide MCoTI-I and assessment of its distribution in the central nervous system2017Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

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

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

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

    Results: An analytical method was successfully developed with linearity R2-values of 0.999 in plasma and 0.988 in brain homogenate. Fu,plasma, fu,brain, Vu,brain, Kp,uu,cell and Kp,uu,brain  was quantified through the methods and equations.

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

  • 40.
    Alchahin, Adele
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Role of the Dorsal Striatum and 5-HT2A receptor in a mouse model of autism2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    BACKGROUND: Some cases of autism spectrum disorder (ASD) are associated with genetic causes. A micro deletion on the human chromosome 16p11.2 is the most common. A mouse model with this deletion demonstrates functional abnormalities in the basal ganglia (BG), mainly the striatum. 5-HT2A receptors are also present in the striatum and may provide substrate for modulating the BG circuitry that possibly has a crucial role in ASD. AIM: To examine neuron activity in the striatum, qualitatively observe the distribution of the 5-HT2A receptor in the striatum and pharmacologically investigate serotonin 5-HT2A involvement in the behavioral abnormalities found in 16p11.2 deletion mice. METHODS: Expression of the gene product of c-fos was measured using immunohistochemistry to provide a measure of neural activity. Autoradiography was used to describe the distribution of the 5-HT2A receptors in the striatum. The effect of risperidone and M100907 on 16p11.2 deletion mice was assayed using the forced swim test. RESULTS: A significant increase in c-fos expression in the dorsal striatum in mutant mice was observed. Both normal and deletion mice exhibited receptor binding to 5-HT2A in the striatum. A significant decrease in mobility in the forced swim test in both mutant and wild type mice was observed only when risperidone was administrated compared to controls and M100907. CONCLUSION: Elevated c-fos expression in the dorsal striatum indicates altered activity in dorsal striatum in this ASD mouse model. 5-HT2A receptor binding in the striatum is qualitatively similar in both genotypes. Risperidone had a greater effect than M100907 in normalizing behavioral response in the swim, yet further dose-response and behavioral studies has to be done for more accurate determinations about the involvement of 5-HT2A as a possible pharmacological target for treatment in autism.

  • 41.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Studies on the importance and characterization of particle fragmentation during tabletting 1985Doctoral thesis, comprehensive summary (Other academic)
  • 42.
    Alderborn, Göran
    et al.
    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.
    Mechanical strength of tablets2008In: Pharmaceutical Dosage Forms: Tablets, Volume 3: Manufacture and Process Control, New York: Informa Healthcare , 2008, 3Chapter in book (Other academic)
  • 43.
    Alenius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Treatment Response in Psychotic Patients in a Naturalistic Setting: Classification, Genes, Drugs, Insight and Social Networks2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

    List of papers
    1. Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Open this publication in new window or tab >>Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Show others...
    2009 (English)In: Comprehensive Psychiatry, ISSN 0010-440X, E-ISSN 1532-8384, Vol. 50, no 5, p. 453-462Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. CONCLUSION: In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98078 (URN)10.1016/j.comppsych.2008.11.001 (DOI)000269251100009 ()19683616 (PubMedID)
    Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2017-12-13Bibliographically approved
    2. Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Open this publication in new window or tab >>Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Show others...
    2008 (English)In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, no 11, p. 884-893Article in journal (Refereed) Published
    Abstract [en]

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

    Keywords
    DRD2, 5-HT2, ABCB1, Cytochrome P-450 CYP2D6, Antipsychotic agents, Schizophrenia
    National Category
    Pharmaceutical Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-98079 (URN)10.1016/j.jpsychires.2007.10.007 (DOI)000258798300002 ()18086475 (PubMedID)
    Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2018-01-13
    3. Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    Open this publication in new window or tab >>Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    2009 (English)Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-98080 (URN)
    Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2011-05-11Bibliographically approved
    4. Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    Open this publication in new window or tab >>Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    2010 (English)In: Social Psychiatry and Psychiatric Epidemiology, ISSN 0933-7954, E-ISSN 1433-9285, Vol. 45, no 5, p. 523-529Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Patients with psychotic symptoms often respond poorly to treatment. Outcomes can be affected by biological, physiological and psychological factors according to the vulnerability-stress model. The patient's coping strategies and beliefs have been correlated with outcomes. OBJECTIVES: To investigate the knowledge and insight in relation to treatment response. METHODS: A naturalistic study was performed using patient interviews and information gathered from patient drug charts. Apart from the rating scales used for classification of treatment response (CANSEPT method), the SPKS knowledge of illness and drugs rating scale was utilized. RESULTS: In the group of patients in functional remission (FR; n = 38), 37% had insight into their illness as compared to 10% among those not in functional remission (non-FR; n = 78; P < 0.01). As much as 23% of the non-FR group had no strategy for responding to warning signs versus 8% in the FR group (P < 0.05). CONCLUSIONS: Better treatment outcomes appear to be associated with better insight into illness, higher knowledge of warning signs and better coping strategies.

    Keywords
    Health knowledge, Treatment outcome, Schizophrenia, Psychotic disorders, Insight
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-123011 (URN)10.1007/s00127-009-0096-3 (DOI)000275422700002 ()19626260 (PubMedID)
    Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
  • 44.
    Alenius, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hartvig, Per
    Lindström, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, no 11, p. 884-893Article in journal (Refereed)
    Abstract [en]

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

  • 45.
    Alhalaweh, Amjad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alzghoul, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Kaialy, Waseem
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Computational predictions of glass-forming ability and crystallization tendency of drug molecules2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 9, p. 3123-3132Article in journal (Refereed)
    Abstract [en]

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

  • 46.
    Alhalaweh, Amjad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alzghoul, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, no 1, p. 312-317Article in journal (Refereed)
    Abstract [en]

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

  • 47.
    Alhalaweh, Amjad
    et al.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Taylor, Lynne S.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.2016In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, p. 172-182Article in journal (Refereed)
    Abstract [en]

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

  • 48.
    Ali, Ersin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Framtida läkemedel bör rikta sig mot väldigt tidiga stadier av Alzheimers sjukdom2012Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
  • 49.
    Ali Haj, Mahmoud
    et al.
    United Arab Emirates University.
    Kazzam, Elsadig
    United Arab Emirates University.
    Amir, Nahid
    United Arab Emirates University.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nicholls, Gary M.
    Otago University .
    Adem, Abdu
    United Arab Emirates University.
    Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel2013In: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, p. 232-Article in journal (Refereed)
    Abstract [en]

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

  • 50.
    Al-kaisy, Muhammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Matthias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Persson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Petterson Bergstrand, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sterby, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wang, Pin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    En förstudie för framtagning av HIV-proteashämmare: Me-too läkemedel till indinavir2012Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The purpose of this report was to develop theoretical analogues of indinavir that ispredicted to bind well to HIV-I protease, wild type and mutants. These analogues aremeant for experimental testing by enzyme assay and cell-based β-galactosidase activityassay to see if they have potential to be new protease inhibitors for HIV. 80 analoguesprovided by the company Syntesdesign AB were analyzed with the software Glide.This was done to find out the binding affinities to HIV-I protease and some of its mostcommon mutations. The results were analyzed to see how different structuralelements contributed to high affinity. 48 new analogues were suggested and alsoanalyzed based on the results of the computer simulations. The 30 analogues with thepredicted highest affinity to the wild type protease and the mutations were selectedand ranked. All but one of these analogues were predicted to have better binding tothe protease than Indinavir.

1234567 1 - 50 of 2207
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf