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  • 1.
    Aarnio, Mikko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Ängeby-Möller, Kristina
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.Manuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: Positron emission tomography with the radioligand [11C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [11C]D-deprenyl´s usefulness as a marker of acute inflammation.

    Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [11C]D-deprenyl, [11C]L-dideuterumdeprenyl and [18F]fluorodeoxyglucose were used.

    Results: No [11C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [11C]D-deprenyl and [11C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [18F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [18F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [11C]D-deprenyl and [11C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

    Conclusions: Contrary to our expectations, of the three tracers only [18F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [11C]D-deprenyl and [11C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

  • 2. Aarons, L
    et al.
    Karlsson, MO
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mentre, F
    Rombout, F
    Steimer, JL
    van Peer, A
    Role of modelling and simulation in Phase I drug development.2001In: Eur J Pharm Sci, Vol. 13, p. 115-Article in journal (Refereed)
  • 3.
    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.

  • 4.
    Abberud, Madelene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Time to first antibiotic administration in The Alfred Emergency and Trauma Centre for suspected febrile neutropenia: a retrospective chart review2012Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Febrile neutropenia (FN) is a frequent complication of chemotherapy use in cancer patients. There is evidence to suggest that the time to antibiotic administration is associated with increase survival and effective clinical outcome. The Australian consensus guidelines for the management of FN in adult cancer patients recommends treatment within 30 minutes to patients with features of systemic compromise. A study performed at The Alfred Hospital in 2010 revealed a median time of 145 minutes to first antibiotic administration. A new guideline was therefore developed and education was implemented. This study was conducted to evaluate the intervention. Aim: To determine time to first antibiotic prescribing and administration for patients with suspected FN presenting to the Alfred Emergency and Trauma centre. Materials and Methods: The electronic medical record of 112 episodes of suspected FN presenting between March and August 2012 were reviewed.  Data were retrospective collected according to a FN data spreadsheet. An observational study were also performed at  The Alfred Emergency and Trauma centre during October and November 2012 to determine time to first antimicrobial prescribing, because this data could not be collected from the electronic medical record. Results: The median time from presentation to antibiotic prescribing was 68 minutes. The median time from presentation to antibiotic administration was 121 minutes. Conclusions: The implementation of the new guidelines has reduced the time with 16.6%, but the target first antibiotic administration within 30 minutes has not been reached.

  • 5.
    AbdelRehim, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Zhang, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Kamel, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hassan, M
    Enantiomer separation of underivatized tocainide and related compounds by CGC using ammonia as carrier gas1996In: JOURNAL OF MICROCOLUMN SEPARATIONS, Vol. 8, p. 151-Article in journal (Refereed)
  • 6.
    Abdel-Rehim, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Influence of ammonia as carrier gas on separation and detection performance in capillary gas chromatography 1994Doctoral thesis, comprehensive summary (Other academic)
  • 7.
    Abdel-Rehim, Mohamed
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hassan, Moustapha
    Capillary gas chromatography of trichlorophenols using ammonia as carrier gas2000In: Journal of High Resolution Chromatography, Vol. 23, p. 156-Article in journal (Refereed)
  • 8.
    Abdi, Hafsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Finns det någon koppling mellan Alzheimers sjukdom och Diabetes Mellitus?2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Alzheimers sjukdom är en neurodegenerativ sjukdom vars orsak är okänd, kännetecknas av en gradvis försämring av kognitiva funktioner. Alzheimers sjukdom och Diabetes Mellitus har flera gemensamma patofysiologiska samband, bland annat insulinresistens. Försämrad insulinsignalering kan leda till kognitiv funktionsförsämring, som i sin tur kan leda till Alzheimers sjukdom. Båda insulin och amyloid-β metaboliseras av insulinnedbrytande enzym (IDE), defekt i IDE kan delvis orsaka amyloid-β ansamlingar. Syftet med detta arbete är att undersöka om försämrad insulinsignalering kan leda till kognitiv försämring och påskynda utvecklingen av Alzheimers sjukdom.

    Jag har gjort en systematisk litteraturöversikt för att undersöka detta. Det är större risk att drabbas av Alzheimers sjukdom om man har Diabetes Mellitus. Man såg ett samband mellan försämrad insulinsignalering och försämrad kognitiv funktion. Förhöjda glukosnivåer var förenade med kognitiv försämring, medan nedsatt glukosnivå inte hade någon betydelse vid kognitiv försämring. Dessutom påskyndar en hög glukosnivå omvandlingen från MCI (mild kognitivs vikt) till Alzheimers sjukdom. Trots detta resultat krävs det mer forskning inom området eftersom olika metoder användes på de olika studierna vilket kan ge ett falskt samband.

  • 9.
    Abdul Amir, Meys
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kvalitetsgranskning av utskrivningsinformation från fyra kirurgavdelningar på Akademiska sjukhuset2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Kvalitetesgranskning av utskrivningsinformation från fyra kirugavdelningar på Akademiska sjukhuset

    Meys Abdul Amir

    Introduktion: Vid utskrivning från kirurgavdelningar förekommer ofta brister i utskrivningsinformation gällande patientens läkemedelsbehandling, vilket medför läkemedelsrelaterad sjuklighet. För att åtgärda detta krävs utdelning av uppdaterad läkemedelslista, fullständig och tydlig information till patienter vid utskrivning samt införande av läkemedelsberättelse i utskrivningsmeddelandet. Läkemedelsberättelse genomförs när läkemedelsförändring utförs under vårdtiden på sjukhuset. Syfte: Syftet med arbetet var att undersöka i vilken utsträckning utskrivningsmeddelande med läkemedelsberättelse skrivs till patienter vid kirurgavdelningar på Akademiska sjukhuset, samt undersöka i vilken utsträckning läkemedelslista skickas med till patienter vid utskrivning och även kontrollera om läkemedelslistorna uppdateras vid utskrivning. Material och metoder: Retrospektiv observationsstudie genom journalgranskning och telefonintervju av alla patienter i alla åldrar utskrivna från alla kirurgavdelningar på Akademiska sjukhuset under december 2015. Resultat: Av 332 patienter som ingick i studien hade läkemedelsförändringar utförts för 176 patienter, och utskrivningsningsmeddelande upprättades till drygt 6,3 % av dessa 176 patienter. Av de 332 patienterna erhöll 60% en uppdaterad läkemedelslista. Telefonintervju genomfördes med 107 patienter och av dessa hade 37% fått en läkemedelslista. Förbättrade resultat observerades hos patienter som fått läkemedelsgenomgång av klinikapotekare vid utskrivning. Konklusion: Rutinen för utskrivningsinformationen är fortfarande bristfällig på de kirurgiska avdelningarna. Flera apotekare behövs på dessa avdelningar, för att kunna minska antal läkemedelsfel efter utskrivning från sjukhuset.

  • 10.
    Abdulahad, Noor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The effects of short-term use of proton pump inhibitors on plasma and salivary nitrate/nitrite and exhaled NO in patients with established coronary artery disease2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Recent studies have suggested several vasoprotective/cardioprotective effects of dietary nitrate (NO3-) and nitrite (NO2-), including blood pressure regulating, antiplatelet effect, enhanced endothelial function and increased oxygen supply in healthy volunteers. There is, on the other hand, concern that an increase in gastric pH may blunt these beneficial effects due to the low pH requirement (pH< 2) for nitric oxide (NO) generation from nitrate in the stomach. This effect has not previously been investigated in 'real life' patients. Aim: To investigate the effects of an increased gastric pH caused by short-term (5 days) use of esomeprazole, a proton pump inhibitor, on plasma and salivary nitrate/nitrite and exhaled NO in patients with established coronary artery disease (CAD). Methods: A total of seven patients with CAD were enrolled in the study. An on-line method was used to determine fractional exhaled concentration of NO (FeNO) at multiple flow rates, data was modeled to estimate alveolar airways NO concentration (Calv) and bronchial NO flux (JNO). Plasma and salivary nitrate/nitrite levels were also analyzed. Results: There was a statistically (P = 0.0469) significant reduction in Calv in the overall patient group after treatment with esomeprazole. There was a trend toward an increase, albeit non-statistically significant (P = 0.0781) in salivary nitrate after treatment with esomeprazole. Conclusion: The major finding in this study is the significant reduction in the alveolar NO concentration in the overall patient group after treatment with esomeprazole. Further research is needed in this area.

  • 11.
    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.

  • 12.
    Abdulla Karim, Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ersättning av två aminosyror i 9S-dioxygenas-allenoxidsyntas av Colletotrichum graminicola samt förkortning av dioxygenasdomänen för 3D-strukturanalys2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Oxylipiner är oxiderade metaboliter av fleromättade fettsyror. Hos svampar är dessa inblandade i kommunikation, reproduktion, reglering av mykotoxinproduktion och modulering av växtförsvarssystemet vid infektion. Colletotrichum graminicola tillhör de mest kända och viktigaste svampar som orsakar skador på grödor. Genen EFQ_27323 från C. graminicola kodar för 9S-dioxygenas-allenoxidsyntas (9S-DOX-AOS) och vid inkubation med linolsyra bildar hydroperoxyoctadekadiensyra (9-HPODE).

     

    Syftet med projektet är dels att ändra kiraliteten av 9S-DOX-AOS i genen EFQ_27323 genom att ersätta aminosyrorna Ile590 och Leu601 mot Gly590 och Phe601, respektive, och dels att förkorta DOX-domänen av enzymet för vidare 3D-strukturanalyser.

     

    Site directed mutagenesis används för mutationer av gener genom PCR-tekniken. Mutanten både transformeras och uttrycks i E.coli (BL21) med hjälp av expressionsvektorn pET101D-TOPO. De uttryckta enzymerna inkuberas med linolsyra (18:2n-6) och aktiviteten och dess kiralitet analyseras med hjälp av LC-MS/MS.

     

    Ersättningen av Ile590 med Gly590 ändrade kiraliteten av 9S-HPODE till 9R-HPODE med 20 % medan dubbelmutanten, d.v.s. Gly590 och Phe601 ändrade kiraliteten med 58 %. Enzymet förlorar sin 9-HPODE aktivitet när en förkortning av DOX-domän utan CYP-domän genomförs.

     

    Specifika aminosyrasubstitutioner i aktivt centrum påverkar regio- och stereoselektiviteten. Aminosyrorna i genen EFQ_27323, Gly590 och Phe601 istället för Ile590 med Leu601 ändrar kiraliteten från 9S-DOX-AOS till 9R-DOX-AOS

  • 13.
    Abdullah, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Validering av narkotikahanteringen för morfin, oxikodon och ketobemidon vid Astrid Lindgrens Barnsjukhus2016Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Validering av narkotikahanteringen för morfin, oxikodon och ketobemidon vid Astrid Lindgrens Barnsjukhus

    Sarah Abdullah

    Fördjupningsprojekt i farmakoterapi 30 hp, Apotekarprogrammet

    Institution för farmaceutisk biovetenskap, Handledare: Per Nydert, Examinator: Margareta Hammalund- Udenaes

    Introduktion: Kontrollerad narkotikaanvändning leder till mindre risk för läkemedelshanteringsfel vilket bidrar till ökad personal- och patientsäkerhet. Syfte: Validering av datauttag från TakeCare samt validering av hanteringen av morfin, oxikodon och ketobemidon på avdelning Q84 och B78 på Astrid Lindgrens Barnsjukhus. Material och metoder: Uttag i narkotikaloggen jämfördes med administreringar i journalsystemet TakeCare. Detta utfördes retrospektivt under 11,5 månader i den kvantitativa studien och prospektivt under ca. en månad i den kvalitativa studien där även orsaker till avvikelserna har studerats. Dessutom jämfördes den dokumenterade kassationen mot den uppskattade kassationen. Resultat: I den retrospektiva studieperioden ingick 93 patienter. Av alla doser i narkotikaloggen fanns på Q84 78,6 % (95 % KI 73,5-83,2) och på B78 85,9 % (95 % KI 81,8-89,4) av doserna i TakeCare. Av totala antalet doser saknades på Q84 21 % (95 % KI 17,0-25,6)* och på B78 5,2 % (95 % KI 3,2-7,99) av doserna i narkotikaloggen. Dessutom förekom det under den retrospektiva studien 38 avvikelser i behållningen vilket var signifikant högre jämfört med fem avvikelser på B78. De huvudsakliga orsakerna till avvikelser mellan uttag och administrering var vård utanför avdelningen (29 % resp. 36 % av alla avvikelser), administrering skedde ur tidigare patientuttag (14 % resp. 14 %), opioidinfusion (34 % resp. 0 %) och behov saknades (0 % resp. 36 %) för Q84 resp. B78. Under hela studieperioden utgjorde den dokumenterade kassationen 0,39 % på Q84 och 0,93 % på B78 av den uppskattade kassationen. Konklusion: Antal doser i TakeCare av alla doser i narkotikaloggen var inte signifikant skild mellan avdelningarna. Däremot var antalet doser som saknades i narkotikaloggen av alla doser signifikant högre på Q84. Detta indikerar att narkotikaloggen var mer välskött på B78. Antalet avvikelser i behållningen var signifikant högre på Q84, vilket indikerar att läkemedelsautomaten på B78 leder till en mer kontrollerad narkotikahantering. Både på avdelning Q84 och B78 var kassationen bristfälligt dokumenterad.

  • 14.
    Abdulmahdi, Rasha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Statinanvändning hos äldre hypertonipatienter med nedsatt njurfunktion

    Rasha Abdulmahdi

    Handledare: Björn Wettermark, Docent, Apotekare, Utvecklingsavdelningen, SLL. Yvonne Freund-Levi, MD PhD Överläkare KI. Tero Shemiekka, överläkare Avdelningen för E-hälsa, SLL. Examinator: Margareta Hammarlund-Udenaes, Professor i farmakokinetik och farmakodynamik. Institutionen för farmaceutisk biovetenskap. Examensarbete i Farmakoterapi D, 30hp, Uppsala universitet.

     

    Introduktion: Äldre patienter löper större risk att utveckla läkemedelsbiverkningar p.g.a. avtagande njurfunktion. Flera publicerade studier tyder på att många patienter läggs in akut på sjukhus för att de använder läkemedel som inte anpassas efter deras njurfunktion. Syfte: Att kartlägga förskrivning av statiner hos äldre hypertonipatienter med avseende på njurfunktion i Skaraborg och sydvästra Stockholms Län. Material och metoder: En tvärsnittstudie baserad på data hämtade från SPCCD (Swedish Primary Care Cardiovascular Database). Patienter ≥ 65 år som hade minst ett registrerat S-kreatinin under år 2006-2008 inkluderades och andelen som hämtade ut statiner under perioden 2006-2009 analyserades. GFR (Glomerular Filtration Rate) beräknades med CKD-EPI-formeln (Chronic Kidney Disease Epidemiology Collaboration). Läkemedelssubstanserna lämplighet eller behov av dosjustering i relation till njurfunktion granskades enligt RenBase, en databas med dokumentation av läkemedel vid nedsatt njurfunktion. Resultat. Totalt identifierades 38 239 individer och av dessa hade 23,8 % behandlats med statiner. De mest förskrivna statinerna var simvastatin (84,2 %) och atorvastatin (10,5 %). Det var signifikant färre (95 % C.I.) som behandlades med de båda statinerna vid en jämförelse mellan GFR < 30 och >30. Det fanns ingen korrelation mellan snittdosering (mg/dag) och njurfunktion. Konklusion: Många äldre hypertonipatienter i primärvården med nedsatt njurfunktion får statinbehandling. Det förefaller dock som om simvastatin inte dosjusteras hos patienter med svårt nedsatt njurfunktion.

                 

  • 15.
    Abdulrasul, Ali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurosteroids and Alzheimer’s disease: Mechanistic studies of neuroprotection and neurogenesis2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Alzheimer’s disease (AD) and its consequent memory and cognitive impairments continue to be unhaltable and incurable to this day. Yet, recent studies demonstrating neuroprotective effects of some neurosteroids have shown a potential of these steroids to modulate AD progression in vitro and in vivo. In the present study, the effects of neurosteroids were studied on hydrogen peroxide (H2O2), as well as staurosporine-induced toxicity in SH-SY5Y neuroblastoma cells. Moreover, underlying mechanisms were investigated. Cell viability was measured with MTT-assay. The results demonstrated that the neurosteroids investigated reduced hydrogen peroxide-induced toxicity. One of the neurosteroid even reduced staurosporine-induced toxicity. Moreover, the present study also showed neurogenic properties for one of the neurosteroid studied.  In conclusion, this report demonstrates that neurosteroids act neuroprotective against hydrogen peroxide-induced toxicity and that one of the neurosteroids studied even acts neuroprotective against staurosporine-induced toxicity and possesses neurogenic effects. 

  • 16. 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.

  • 17.
    Abelo, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eriksson, UG
    Karlsson, MO
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larsson, H
    Gabrielsson, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A turnover model of irreversible inhibition of gastric acid secretion byomeprazole in the dog.2000In: J Pharmacol Exp Ther, Vol. 295, p. 662-Article in journal (Refereed)
  • 18.
    Abelo, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gabrielsson, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Holstein, B
    Eriksson, UG
    Holmberg, J
    Karlsson, MO
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacodynamic modelling of reversible gastric acid pump inhibition indog and man.2001In: Eur J Pharm Sci, Vol. 14, p. 339-Article in journal (Refereed)
  • 19.
    Abelo, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Holstein, B
    Eriksson, UG
    Gabrielsson, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, MO
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gastric acid secretion in the dog: a mechanism-based pharmacodynamic modelfor histamine stimulation and irreversible inhibition by omeprazole.2002In: J Pharmacokinet Pharmacodyn, Vol. 29, p. 365-Article in journal (Refereed)
  • 20.
    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.

  • 21.
    Abood, Ekhlas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Identifying Medication History Errors at Iraqi Hospital Admissions Using The Swedish-LIMM model2016Independent thesis Advanced level (degree of Master (One Year)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    Abstract

    Background and Objective: An accurate medication history list is an integral part of the patient assessment at hospital admission. The objective of the study was to describe the frequency, type, and predictors of unintentional medication errors and to evaluate the quality of the clinical pharmacy services focusing on the acceptance of the recommendations made by the clinical pharmacist.

    Setting and methods: A descriptive study was conducted at two internal medicine wards at Baghdad Teaching Hospital in Iraq using Lund Integrated Medicines Management (LIMM)-based medication reconciliation. The study pharmacist conducted medication interviews for patients shortly after hospital admission to obtain the most accurate pre-admission medication history list. This list was compared with the medication list in the patient’s medical chart. Intended addition, withdrawal of a drug, or changes to the dose/ dosage form in the patient’s medical list was considered as medication discrepancies. However, medication discrepancies were considered as medication errors based on no identified clinical reason.

    Results: A total of 114 patients were included in this study. Over two-thirds of the study patients (73.7%) experienced 215 medication errors identified by a clinical pharmacist conducting medication reconciliation. Most errors were omission (87.9%). Cardiovascular agents followed by NSAID were commonly in error (53%) and (10.2%) respectively. In a logistic regression model, age (odds ratio (OR), 1.055: 95% confidence interval (CI) 1.010 - 1.102), female gender (OR, 3.468: 95% CI 1.232- 9.761) and number of medications at admission (OR, 0.810: 95% CI 0.681-0.963) were predictors for medication history errors at admission.

    Conclusions: Medication errors at the time of hospital admission are common and undetected.  A structured approach like the LIMM-based medication reconciliation at Iraqi hospital is needed to detect these errors.

  • 22.
    Aboye, Teshome L.
    et al.
    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, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis, Cyclization and Oxidative folding of backbone engineered Cyclotides2010Conference paper (Refereed)
  • 23.
    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.

  • 24.
    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
  • 25.
    Aboye, Teshome Leta
    et al.
    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, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Design, synthesis, structural and biological evaluation of backbone-engineered cyclotidesManuscript (preprint) (Other academic)
  • 26.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    University of Queensland, Institute for Molecular Bioscience.
    Burman, Robert
    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, Division of Pharmacognosy.
    Synthesis and Oxidative Folding of Cyclic Cystine Knot Peptides: Towards Backbone Engineering2010In: Peptides 2010: Tales of Peptides Proceedings of the Thirty-First European Peptide Symposium / [ed] Michal Lebl, Morten Meldal, Knud J. Jensen, Thomas Høeg-Jensen, European Peptide Society , 2010, p. 142-143Conference paper (Refereed)
  • 27.
    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.

  • 28.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Clark, Richard. J.
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Goransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2.2008In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 74, no 9, p. 1158-1158Article in journal (Refereed)
  • 29.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    University of Queensland, Institute for Molecular Bioscience.
    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, Division of Pharmacognosy.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O22008In: Peptides 2008: Chemistry of Peptides in Life Science Technology and MedicineProceedings of The Thirtieth European Peptide Symposium / [ed] Hilkka Lankinen, The Finnish Peptide Society and The European Peptide Society , 2008, p. 280-281Conference paper (Refereed)
  • 30.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, Johan
    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, G. Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoiManuscript (preprint) (Other academic)
  • 31. Abrahamsson, B
    et al.
    Lennernas, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Application of the biopharmaceutic classification system now and in the future2003In: Drug Bioavailability – Estimation of Solubility, Permeability, Absorption and Bioavailability, Wiley , 2003Chapter in book (Other scientific)
  • 32.
    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)
  • 33.
    Abrahamsson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Post Authorization Safety Studies (PASS) & Patient Support Programs (PSP): Läkemedelsföretagens säkerhetsverktyg efter lansering2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: I juli 2012 uppdaterades regelverken för farmakovigilans inom Europa och flera förändringar gjordes i de bestämmelser som rör säkerhetsstudier på godkända läkemedel. En sammanställning av dessa behövdes för att lyfta fram viktiga bestämmelser och ge en tydligare överblick av de myndighetskrav som berör PASS (Post-Authorization Safety Studies) och PSP (Patient Support Programs).

     

    Syfte: Projektet syftar till att analysera och tolka regelverk och riktlinjer gällande PASS och PSP inom Europa samt utreda vad som gäller för PASS i de skandinaviska länderna. Detta för att lyfta fram viktiga bestämmelser och underlätta tolkningen för berörda företag.

     

    Material och metoder: Huvuddelen av projektet bestod av en litteraturstudie där fokus låg på lagar och riktlinjer inom Europa. Informationsinhämtning skedde även genom intervjuer med personal på Bayer AB och Läkemedelsverket. Jämförelser har sedan gjorts mellan svenska, norska och danska regelverk.

     

    Resultat: Myndighetskraven för PASS och PSP skiljer sig åt i vissa avseenden. Etikgodkännande krävs för PASS men inte för PSP och slutrapporten från en PASS granskas av läkemedelsmyndighet medan PSP inte ger någon slutrapport. För PASS krävs i Sverige och Norge ett etikgodkännande vilket inte krävs i Danmark. I Danmark ska dokumentation om studien skickas till läkemedelsmyndigheten om Danmark är referensland eller rapportör för produkten. I Sverige och Norge krävs ingen kommunikation med läkemedelsmyndigheten.

     

    Konklusion: PASS syftar till att studera säkerheten hos läkemedel medan PSP primärt är ett stöd för patientvården i vilket vissa säkerhetsaspekter kan fångas upp sekundärt. Trots att regelverken rörande farmakovigilans gäller för samtliga EU-länder har olika tolkningar gjorts i de skandinaviska länderna och de lokala regelverken skiljer sig åt i vissa avseenden.

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

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

  • 35.
    Abrantes, João A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Korth-Bradley, J.
    Pfizer Inc, Collegeville, PA USA..
    Harnisch, L.
    Pfizer Ltd, Global Clin Pharmacol, Sandwich, Kent, England..
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 6, p. 977-988Article in journal (Refereed)
    Abstract [en]

    This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

  • 36. Abs, Roger
    et al.
    Feldt-Rasmussen, Ulla
    Mattsson, Anders F
    Monson, John P
    Bengtsson, Bengt-Ake
    Goth, M I
    Wilton, Patrick
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis.2006In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 155, no 1, p. 79-90Article in journal (Refereed)
    Abstract [en]

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

  • 37. Abs, Roger
    et al.
    Mattsson, Anders F
    Bengtsson, Bengt-Ke
    Feldt-Rasmussen, Ulla
    Goth, Miklos I
    Koltowska-Häggström, Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Monson, John P
    Verhelst, Johan
    Wilton, Patrick
    Isolated growth hormone (GH) deficiency in adult patients: Baseline clinical characteristics and responses to GH replacement in comparison with hypopituitary patients. A sub-analysis of the KIMS database.2005In: Growth Horm IGF Res, ISSN 1096-6374, Vol. 15, no 5, p. 349-59Article in journal (Refereed)
  • 38. Abt, G
    et al.
    Vaghef, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gebhart, E
    Dahlgren, CV
    Hellman, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The role of N-acetylcysteine as a putative radioprotective agent on X-ray-induced DNA damage as evaluated by alkaline single-cell gel electrophoresis1997In: MUTATION RESEARCH-DNA REPAIR, Vol. 384, p. 55-Article in journal (Refereed)
  • 39. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne M.
    Wikman, Anna S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rahnasto, Minna
    Juvonen, Risto O.
    Vepsalainen, Jouko
    Raunio, Hannu
    Ng, Jack C.
    Lang, Matti A.
    Metabolism of bilirubin by human cytochrome P450 2A62012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 261, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic "Bilirubin Oxidase" (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K-i of 2.231 mu M. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301,315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human "Bilirubin Oxidase" where bilirubin is potentially a substrate and a regulator of the enzyme.

  • 40. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne Maioha
    Aganovic, Simona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ng, Jack C.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Inducible bilirubin oxidase: A novel function for the mouse cytochrome P450 2A52011In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 257, no 1, p. 14-22Article in journal (Refereed)
    Abstract [en]

    We have previously shown that bilirubin (BR), a breakdown product of haem, is a strong inhibitor and a high affinity substrate of the mouse cytochrome P450 2A5 (CYP2A5). The antioxidant BR, which is cytotoxic at high concentrations, is potentially useful in cellular protection against oxygen radicals if its intracellular levels can be strictly controlled. The mechanisms that regulate cellular BR levels are still obscure. In this paper we provide preliminary evidence for a novel function of CYP2A5 as hepatic "BR oxidase''. A high-performance liquid chromatography/electrospray ionisation mass spectrometry screening showed that recombinant yeast microsomes expressing the CYP2A5 oxidise BR to biliverdin, as the main metabolite, and to three other smaller products with m/z values of 301,315 and 333. The metabolic profile is significantly different from that of chemical oxidation of BR. In chemical oxidation the smaller products were the main metabolites. This suggests that the enzymatic reaction is selective, towards biliverdin production. Bilirubin treatment of primary hepatocytes increased the CYP2A5 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A5 compared to cells treated only with CHX. Collectively, the observations suggest that the CYP2A5 is potentially an inducible "BR oxidase" where BR may accelerate its own metabolism through stabilization of the CYP2A5 protein. It is possible that this metabolic pathway is potentially part of the machinery controlling intracellular BR levels in transient oxidative stress situations, in which high amounts of BR are produced.

  • 41. 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.

  • 42. Abu-Bakar, A'edah
    et al.
    Moore, Michael R
    Lang, Matti A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5.2005In: Biochem Pharmacol, ISSN 0006-2952, Vol. 70, no 10, p. 1527-35Article in journal (Refereed)
  • 43.
    Abu-Bakar, Aedah
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Satarug, Soisungwan
    NCRET, UQ.
    Marks, Goeffrey
    NCRET, UQ.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Acute cadmium chloride administration induces hepatic and renal CYP2A5 mRNA, protein and activity in the mouse: involvement of transcription factor Nrf22004In: Tox letters, Vol. 148, p. 199-210Article in journal (Refereed)
  • 44.
    Acharya, Chayan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Turkyilmaz, Gulbeyaz Yildiz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Ege Univ, Fac Pharm, Dept Biopharmaceut & Pharmacokinet, TR-35100 Izmir, Turkey..
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A diagnostic tool for population models using non-compartmental analysis: The ncappc package for R2016In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 127, p. 83-93Article in journal (Refereed)
    Abstract [en]

    Background and objective: Non-compartmental analysis (NCA) calculates pharmacokinetic (PK) metrics related to the systemic exposure to a drug following administration, e.g. area under the concentration time curve and peak concentration. We developed a new package in R, called ncappc, to perform (i) a NCA and (ii) simulation-based posterior predictive checks (ppc) for a population PK (PopPK) model using NCA metrics. Methods: The nca feature of ncappc package estimates the NCA metrics by NCA. The ppc feature of ncappc estimates the NCA metrics from multiple sets of simulated concentration time data and compares them with those estimated from the observed data. The diagnostic analysis is performed at the population as well as the individual level. The distribution of the simulated population means of each NCA metric is compared with the corresponding observed population mean. The individual level comparison is performed based on the deviation of the mean of any NCA metric based on simulations for an individual from the corresponding NCA metric obtained from the observed data. The ncappc package also reports the normalized prediction distribution error (NPDE) of the simulated NCA metrics for each individual and their distribution within a population. Results: The ncappc produces two default outputs depending on the type of analysis performed, i.e., NCA and PopPK diagnosis. The PopPK diagnosis feature of ncappc produces 8 sets of graphical outputs to assess the ability of a population model to simulate the concentration time profile of a drug and thereby evaluate model adequacy. In addition, tabular outputs are generated showing the values of the NCA metrics estimated from the observed and the simulated data, along with the deviation, NPDE, regression parameters used to estimate the elimination rate constant and the related population statistics. Conclusions: The ncappc package is a versatile and flexible tool-set written in R that successfully estimates NCA metrics from concentration time data and produces a comprehensive set of graphical and tabular output to summarize the diagnostic results including the model specific outliers. The output is easy to interpret and to use in evaluation of a population PK model. ncappc is freely available on CRAN (http://crantoprojectorg/web/packages/ncappc/index.html/) and GitHub (https://github.comicacha0227/ncappc/). 

  • 45. 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.

  • 46.
    Acuna, UM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Atha, DE
    Ma, J
    Nee, MH
    Kennelly, EJ
    Antioxidant capacities of ten edible North American plants.2002In: Phytother Res, Vol. 16, p. 63-Article in journal (Refereed)
  • 47.
    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.

  • 48.
    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)
  • 49. Adem, Abdu
    et al.
    Al Haj, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Benedict, Sheela
    Yasin, Javed
    Nagelkerke, Nicolas
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yandle, Tim G.
    Frampton, Chris M.
    Lewis, Lynley K.
    Nicholls, M. Gary
    Kazzam, Elsadig
    ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e57806-Article in journal (Refereed)
    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.

  • 50.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor2017In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, p. 947-955Article in journal (Refereed)
    Abstract [en]

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

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