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  • 151. Alder, JT
    et al.
    Johansson, AM
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Strange, PG
    The relative binding affinities of a series of 2-(dipropylamino)tetralins at the human 5-HT1A receptor expressed in CHO cells2000Ingår i: Br. J. Pharmacol., Vol. 129, s. 242-Artikel i tidskrift (Refereegranskat)
  • 152.
    Alderborn, A
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Siegbahn, A
    Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wadelius, C
    Institutionen för genetik och patologi.
    Venous thrombosis: factor V G1691A genotyping related to APC resistance as measured by 2 methods1997Ingår i: Eur J Haematol, Vol. 58, s. 229-Artikel i tidskrift (Refereegranskat)
  • 153.
    Alderborn, G
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A novel approach to derive a compression parameter indicating effective particle deformability.2003Ingår i: Pharm Dev Technol, Vol. 8, s. 367-Artikel i tidskrift (Refereegranskat)
  • 154.
    Alderborn, G
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Tablets and compaction2001Ingår i: Pharmaceutics - The science of dosage form design, Churchill Livingstone, London , 2001, Vol. 2Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 155.
    Alderborn, G
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Tablets and compaction2007Ingår i: Aulton´s Pharmaceutics - The design and manufacture of medicines. 3rd ed., Churchill Livingstone, Edinburgh , 2007Kapitel i bok, del av antologi (Refereegranskat)
  • 156.
    Alderborn, G
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The effect of particle size and shape on the compactibility of powders1996Ingår i: Pharmaceutical Powder Compaction Technology, Marcel Dekker Inc., New York , 1996Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 157.
    Alderborn, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Studies on the importance and characterization of particle fragmentation during tabletting 1985Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 158.
    Alderborn, Göran
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bjork, Erik
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Castensson, Staffan
    Johansson, Mats
    Waltersson, Jan-Olof
    Utformning av läkemedel2000Bok (Övrigt vetenskapligt)
  • 159.
    Alderborn, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Frenning, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mechanical strength of tablets2008Ingår i: Pharmaceutical Dosage Forms: Tablets, Volume 3: Manufacture and Process Control, New York: Informa Healthcare , 2008, 3Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 160.
    Alderborn, Göran
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nystrom, Christer
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pharmaceutical Powder Compaction Technology1996Bok (Övrigt vetenskapligt)
  • 161.
    Alderborn, Göran
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Wikberg, Martin
    Material properties of importance for powder volume reduction and compact strength1996Ingår i: Pharmaceutical Powder Compaction Technology, Marcel Dekker, Inc. , 1996Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 162.
    Alenius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Treatment Response in Psychotic Patients in a Naturalistic Setting: Classification, Genes, Drugs, Insight and Social Networks2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Öppna denna publikation i ny flik eller fönster >>Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Visa övriga...
    2009 (Engelska)Ingår i: Comprehensive Psychiatry, ISSN 0010-440X, E-ISSN 1532-8384, Vol. 50, nr 5, s. 453-462Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98078 (URN)10.1016/j.comppsych.2008.11.001 (DOI)000269251100009 ()19683616 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Öppna denna publikation i ny flik eller fönster >>Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    DRD2, 5-HT2, ABCB1, Cytochrome P-450 CYP2D6, Antipsychotic agents, Schizophrenia
    Nationell ämneskategori
    Farmaceutiska vetenskaper Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-98079 (URN)10.1016/j.jpsychires.2007.10.007 (DOI)000258798300002 ()18086475 (PubMedID)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2018-01-13
    3. Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    Öppna denna publikation i ny flik eller fönster >>Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    2009 (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Identifikatorer
    urn:nbn:se:uu:diva-98080 (URN)
    Tillgänglig från: 2009-02-11 Skapad: 2009-02-11 Senast uppdaterad: 2011-05-11Bibliografiskt granskad
    4. Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    Öppna denna publikation i ny flik eller fönster >>Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    2010 (Engelska)Ingår i: Social Psychiatry and Psychiatric Epidemiology, ISSN 0933-7954, E-ISSN 1433-9285, Vol. 45, nr 5, s. 523-529Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Health knowledge, Treatment outcome, Schizophrenia, Psychotic disorders, Insight
    Nationell ämneskategori
    Psykiatri
    Identifikatorer
    urn:nbn:se:uu:diva-123011 (URN)10.1007/s00127-009-0096-3 (DOI)000275422700002 ()19626260 (PubMedID)
    Tillgänglig från: 2010-04-22 Skapad: 2010-04-22 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
  • 163.
    Alenius, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hartvig, Per
    Lindström, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset.
    Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders2010Ingår i: Social Psychiatry and Psychiatric Epidemiology, ISSN 0933-7954, E-ISSN 1433-9285, Vol. 45, nr 5, s. 523-529Artikel i tidskrift (Refereegranskat)
    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.

  • 164.
    Alenius, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hartvig, Per
    Sundquist, Staffan
    Lindström, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission2009Ingår i: Comprehensive Psychiatry, ISSN 0010-440X, E-ISSN 1532-8384, Vol. 50, nr 5, s. 453-462Artikel i tidskrift (Refereegranskat)
    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.

  • 165.
    Alenius, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hartvig Honoré, Per
    Lindström, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset.
    Hammarlund-Udenaes, Margareta
    Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients2009Artikel i tidskrift (Refereegranskat)
  • 166.
    Alenius, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Dahl, Marja-Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Hartvig, Per
    Lindström, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008Ingår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikel i tidskrift (Refereegranskat)
    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.

  • 167.
    Alexandersson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Clinical data analyses of T-DM1, an anitbody drug conjugate for metastatic breast cancer2013Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Användningen av Socialstyrelsens ”Indikatorer för god

     läkemedelsterapi hos äldre” i Värmland

    Erika Markberg

    Handledare: Anna Karin Lidehäll. Examinator: Margareta Hammarlund-Udenaes.

     Institutionen för farmaceutisk biovetenskap. Avdelningen för farmakokinetik och läkemedelsterapi. 30 hp.

    Introduktion: Andelen äldre personer blir allt större, vilket gör det viktigare att de äldres läkemedel uppmärksammas. För att hjälpa förskrivarna i detta arbete har Socialstyrelsen tagit fram indikatorer som skall ge god läkemedelsterapi hos de äldre.

    Syfte: Att utvärdera vetskapen om och följsamheten till Socialstyrelsens indikatorer för äldre personer hos läkare verksamma vid vårdcentralen respektive på sjukhuset samt att utvärdera om läkemedelsförskrivningen vid ett särskilt boende i Värmland är anpassad efter Socialstyrelsens indikatorer för läkemedelsförskrivning till äldre personer.

    Material och metoder: En enkät skickades ut till ett sjukhus och en vårdcentral där förskrivarna fick svara på denna. Läkemedelslistor hämtades ifrån ett särskilt boende och utvärderades.

    Resultat: Alla förskrivarna på vårdcentralen men endast 18 % av förskrivarna vid sjukhuset hade kännedom om indikatorerna. Förskrivarna på sjukhuset ville ha mer information om Socialstyrelsens indikatorer. Läkemedelslistorna till 15 % av de totalt 47 personerna innehöll ett eller flera läkemedel som klassades som olämpliga. De olämpliga läkemedel som förekom var propiomazin, långverkande bensodiazepin eller läkemedel med antikolinerga effekter. Slutsats: Förskrivarnas kännedom om Socialstyrelsens indikatorer skiljer sig beroende på om de jobbar på vårdcentral eller på sjukhus. Läkemedelslistorna följde Socialstyrelsens indikatorer i stor utsträckning.

  • 168.
    Alexandersson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Clinical data analyses of T-DM1, an antibody drug conjugate for metastatic breast cancer2013Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
  • 169.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions2019Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, nr 1, s. 252-259Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).

  • 170.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Kaialy, Waseem
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Computational predictions of glass-forming ability and crystallization tendency of drug molecules2014Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, nr 9, s. 3123-3132Artikel i tidskrift (Refereegranskat)
    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.

  • 171.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability2015Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, nr 1, s. 312-317Artikel i tidskrift (Refereegranskat)
    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.

  • 172.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    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.2016Ingår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, s. 172-182Artikel i tidskrift (Refereegranskat)
    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.

  • 173. Alhalaweh, Amjad
    et al.
    Sokolowski, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Rodriguez-Hornedo, Nair
    Velaga, Sitaram P.
    Solubility Behavior and Solution Chemistry of Indomethacin Cocrystals in Organic Solvents2011Ingår i: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 11, nr 9, s. 3923-3929Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin-saccharin (IND-SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND-SAC cocrystals was compared with that of indomethacin-nicotinamide (IND-NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND-SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND-SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND-NIC cocrystals were more soluble than the IND-SAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior.

  • 174. Al-Henhena, Nawal
    et al.
    Khalifa, Shaden A. M.
    Ying, Rozaida Poh Yuen
    Hassandarvish, Pouya
    Rouhollahi, Elham
    Al-Wajeeh, Nahla Saeed
    Ali, Habibah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon2015Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikel-id 13312Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and beta-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

  • 175.
    Al-Henhena, Nawal
    et al.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia.;Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Ying, Rozaida Poh Yuen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Ismail, Salmah
    Univ Malaya, Fac Sci, Inst Biol Sci, Kuala Lumpur 50603, Malaysia..
    Hamadi, Riad
    Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Shawter, Abdrabu N.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Idris, Azila Mohd
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Azizan, Ainnul
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Al-Wajeeh, Nahla Saeed
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Abdulla, Mahmood Ameen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo2015Ingår i: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 15, artikel-id 419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. Methods: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. Results: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down-regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. Conclusion: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade.

  • 176. Al-Henhena, Nawal
    et al.
    Ying, Rozaida Poh Yuen
    Ismail, Salmah
    Najm, Wala
    Khalifa, Shaden A. M.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Abdulla, Mahmood Ameen
    Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikel-id e111118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and beta-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

  • 177.
    Alho, Hannu
    et al.
    Univ Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Dept Internal Med, Helsinki, Finland..
    Jansen, Jakob
    Arhus Municipal, Ctr Addict Treatment, Aarhus, Denmark..
    Krajci, Peter
    Oslo Univ Hosp, Div Mental Hlth & Addict, Dept Subst Use Disorder Treatment, Oslo, Norway..
    Littlewood, Richard
    Appliedstrategic, London, England..
    Runarsdottir, Valgendur
    Vogur Hosp, SAA Ctr Addict Treatment, Reykjavik, Iceland..
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Misuse and diversion of agonist opioid treatment medicines: assessment of the scale of the problem and review of the changing environment for care in the Nordic countries2015Ingår i: Heroin Addiction and Related Clinical Problems, ISSN 1592-1638, Vol. 17, nr 5, s. 43-49Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Background: Opioid addiction is effectively treated via a multidisciplinary approach including agonist opioid treatment (AOT) and psychosocial intervention. Misuse and diversion of AOT medicines such as methadone and mono-buprenorphine comprise a significant problem occurring in the Nordic countries with some of the highest frequencies in Europe. Misuse and diversion are associated with poor treatment compliance and increases in risk of blood-borne infections, crime, and mortality. Regulations and guidelines for provision of AOT medication vary among the Nordic countries. Aim: The extent and impact of misuse and diversion in the Nordic countries has not been documented in the literature. This review of local sources summarizes the extent and impact of misuse and diversion of AOT medication to provide a basis for improving outcomes in opioid addiction care. Methods: PubMed was searched using the terms "methadone" or "buprenorphine" and "misuse" or "diversion". Titles and abstracts of search results were inspected for location and relevance. Government sources and mainstream media were also searched for relevant reports. Results: Misuse and diversion of AOT medicines is a significant issue in the Nordic countries; these opioids are available outside of treatment and are misused, including by young addicts. To address this problem, changes in medicines used in treatment in Finland and Iceland have already been implemented and considerations are under way in Norway and Sweden. Conclusions: All persons involved in AOT should take action to better understand AOT medication misuse and diversion as this can lead to a step change improvement in outcomes.

  • 178.
    Alhuseinalkhudhur, Ali
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Frejd, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kinetic Analysis of the HER2-binding ABY-025 Affibody Using Dynamic PET in Patients with Metastatic Breast Cancer2018Ingår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, s. S457-S457Artikel i tidskrift (Övrigt vetenskapligt)
  • 179.
    Ali, Ehood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Harvard Medical school / Boston Children's Hospital.
    The Role of the Glycine Receptor’s Alpha 2Subunit in the Behavior of Mice2014Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 180.
    Ali, Ersin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Framtida läkemedel bör rikta sig mot väldigt tidiga stadier av Alzheimers sjukdom2012Självständigt arbete på grundnivå (kandidatexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 181.
    Ali Haj, Mahmoud
    et al.
    United Arab Emirates University.
    Kazzam, Elsadig
    United Arab Emirates University.
    Amir, Nahid
    United Arab Emirates University.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    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 camel2013Ingår i: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, s. 232-Artikel i tidskrift (Refereegranskat)
    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.

  • 182. Ali, M Al Haj
    et al.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Chandranath, S I
    Dhanasekaran, S
    Tariq, Saeed
    Petroianu, G
    Hasan, M Y
    Adeghate, Ernest A
    Adem, A
    Distribution of neuroendocrine cells in the small and large intestines of the one-humped camel (Camelus dromedarius)2007Ingår i: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 41, nr 5, s. 293-299Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The distribution and relative frequency of neuroendocrine cells in the small and large intestines of one-humped camel were studied using antisera against 5-hydroxytryptamine (5-HT), cholecystokinin (CCK-8), somatostatin (SOM), peptide tyrosine tyrosine (PYY), gastric inhibitory polypeptide (GIP), neuronal nitric oxide synthase (nNOS), gastrin releasing peptide (GRP), substance P (SP), and neurokinin A (NKA). Among these cell types, CCK-8 immunoreactive (IR) cells were uniformly distributed in the mucosa, while others showed varied distribution in the villi or crypts of the small intestine. Immunoreactive cells like 5HT, CCK-8, and SOM showed peak density in the villi and crypts of the small intestine and in the colonic glands of the large intestine, while cells containing SP were discerned predominately in the crypts. 5-HT, CCK-8 and SOM cells were mainly flask-shaped and of the open-variety, while PYY and SP immunoreactive cells were mainly rounded or basket-shaped and of the closed variety. Basically the distribution pattern of the endocrine cells in the duodenum, jejunum and colon of the one-humped camel is similar to that of other mammals. Finally, the distribution of these bioactive agents may give clues as to how these agents aid in the function of the intestinal tract of this desert animal.

  • 183. Ali, M. Al-Haj
    et al.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Chandranath, S. I.
    Ponery, A. S.
    Adem, A.
    Adeghate, E.
    Effect of high-calorie diet on the prevalence of diabetes mellitus in the one-humped camel (Camelus dromedarius)2006Ingår i: DIABETES MELLITUS AND ITS COMPLICATIONS - MOLECULAR MECHANISMS, EPIDEMIOLOGY, AND CLINICAL MEDICINE / [ed] Adeghate E; Saadi H; Adem A; Obineche E, 2006, Vol. 1084, s. 402-410Konferensbidrag (Refereegranskat)
    Abstract [en]

    The one-humped camel is a typical desert animal. It has the capability of withstanding the harsh climatic changes and the scarcity of food and water, in addition to the high-ambient temperature. The prevalence of diabetes mellitus in two different groups of the one-humped camel, group (A) control (n = 102) camels and group (B) high-calorie diet-fed camels (n = 103), in Al-Ain region (UAE) was studied using biochemical and radioirnmunoassay techniques. In this article, 7% of the control camels have diabetes mellitus (blood glucose level: >= 140 mg/dL) compared to 21% of the high-calorie-fed camels. Plasma insulin level was significantly (P < 0.05) lower in group B compared to group A. The low insulin level in camels consuming high-caloric diet could be a sign of exhaustion of pancreatic beta cells. The hematological parameters were nearly similar in both groups and no significant differences were seen. Liver and kidney enzymes were normal in both groups. Iron and copper were significantly (P < 0.005) higher in the high-calorie-fed camels compared with the control. Our study indicates that high-caloric feed consumption in camels is associated with the development of disorders in glucose metabolism leading to diabetes mellitus.

  • 184.
    Ali, Mahmoud Alhaj
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Adem, Abdu
    Chandranath, Irwin S.
    Benedict, Sheela
    Pathan, Javed Y.
    Nagelkerke, Nicolas
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lewis, Lynley K.
    Yandle, Tim G.
    Nicholls, Gary M.
    Frampton, Chris M.
    Kazzam, Elsadig
    Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 5, s. e37299-Artikel i tidskrift (Refereegranskat)
    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.

  • 185.
    Ali, Sara E.
    et al.
    German Univ Cairo, Fac Pharm & Biotechnol, Dept Pharmaceut Biol, New Cairo 12613, Egypt.
    El Gedaily, Rania A.
    Cairo Univ, Fac Pharm, Pharmacognosy Dept, Kasr el Aini St, Cairo 11562, Egypt.
    Mocan, Andrei
    Iuliu Hatieganu Univ Med & Pharm, Dept Pharmaceut Bot, Cluj Napoca 400337, Romania.
    Farag, Mohamed A.
    Cairo Univ, Fac Pharm, Pharmacognosy Dept, Kasr el Aini St, Cairo 11562, Egypt;Amer Univ Cairo, Sch Sci & Engn, Dept Chem, New Cairo 11835, Egypt.
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Menoufia Univ, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Profiling Metabolites and Biological Activities of Sugarcane (Saccharum officinarum Linn.) Juice and Its Product Molasses via a Multiplex Metabolomics Approach2019Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, nr 5, artikel-id 934Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sugarcane (Saccharum officinarum L.) is an important perennial grass in the Poaceae family cultivated worldwide due to its economical and medicinal value. In this study, a combined approach using mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy was employed for the large-scale metabolite profiling of sugarcane juice and its by-product molasses. The polyphenols were analysed via UPLC-UV-ESI-MS, whereas the primary metabolites such as sugars and organic and amino acids were profiled using NMR spectroscopy and gas chromatography/mass spectrometry (GC/MS). UPLC/MS was more effective than NMR spectroscopy or GC/MS for determining differences among the metabolite compositions of the products. Under the optimized conditions, UPLC/MS led to the identification of 42 metabolites, including nine flavonoids, nine fatty acids, and two sterols. C/O Flavone glycosides were the main subclass detected, with tricin-7-O-deoxyhexosyl glucuronide being detected in sugarcane and molasses for the first time. Based on GC/MS analysis, disaccharides were the predominant species in the sugarcane juice and molasses, with sucrose accounting for 66% and 59%, respectively, by mass of all identified metabolites. The phenolic profiles of sugarcane and molasses were further investigated in relation to their in vitro antioxidant activities using free radical scavenging assays such as 2,2-Diphenyl-1-picrylhydrazyl free radical-scavenging ability (DPPH), Trolox equivalent antioxidant capacity (TEAC) and ferric reducing antioxidant power (FRAP). In view of its higher total phenolic content (TPC) (196 +/- 2.1 mg GAE/100 g extract) compared to that of sugarcane juice (93 +/- 2.9 mg GAE/100 g extract), molasses exhibited a substantially higher antioxidant effect. Interestingly, both extracts were also found to inhibit alpha-glucosidase and alpha-amylase enzymes, suggesting a possible antihyperglycaemic effect. These findings suggest molasses may be a new source of natural antioxidants for functional foods.

  • 186.
    Alin, MH
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ashton, M
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kihamia, CM
    Mtey, GJ
    Bjorkman, A
    Clinical efficacy and pharmacokinetics of artemisinin monotherapy and incombination with mefloquine in patients with falciparum malaria.1996Ingår i: Br J Clin Pharmacol, Vol. 41, s. 587-Artikel i tidskrift (Refereegranskat)
  • 187. Alison, Lauriane
    et al.
    Demirörs, Ahmet F
    Tervoort, Elena
    Teleki, Alexandra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Nutritional R&D Center Formulation and Application, DSM Nutritional Products Ltd., P.O. Box 2676, 4002 Basel, Switzerland.
    Vermant, Jan
    Studart, Andre R
    Emulsions Stabilized by Chitosan-Modified Silica Nanoparticles: pH Control of Structure-Property Relations2018Ingår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 34, nr 21, s. 6147-6160Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In food-grade emulsions, particles with an appropriate surface modification can be used to replace surfactants and potentially enhance the stability of emulsions. During the life cycle of products based on such emulsions, they can be exposed to a broad range of pH conditions and hence it is crucial to understand how pH changes affect stability of emulsions stabilized by particles. Here, we report on a comprehensive study of the stability, microstructure, and macroscopic behavior of pH-controlled oil-in-water emulsions containing silica nanoparticles modified with chitosan, a food-grade polycation. We found that the modified colloidal particles used as stabilizers behave differently depending on the pH, resulting in unique emulsion structures at multiple length scales. Our findings are rationalized in terms of the different emulsion stabilization mechanisms involved, which are determined by the pH-dependent charges and interactions between the colloidal building blocks of the system. At pH 4, the silica particles are partially hydrophobized through chitosan modification, favoring their adsorption at the oil-water interface and the formation of Pickering emulsions. At pH 5.5, the particles become attractive and the emulsion is stabilized by a network of agglomerated particles formed between the droplets. Finally, chitosan aggregates form at pH 9 and these act as the emulsion stabilizers under alkaline conditions. These insights have important implications for the processing and use of particle-stabilized emulsions. On one hand, changes in pH can lead to undesired macroscopic phase separation or coalescence of oil droplets. On the other hand, the pH effect on emulsion behavior can be harnessed in industrial processing, either to tune their flow response by altering the pH between processing stages or to produce pH-responsive emulsions that enhance the functionality of the emulsified end products.

  • 188.
    Aljaderi, Russil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Behandling av CNS-metastaserad bröstcancer i Uppsala2014Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Bröstcancer är den näst mest vanliga orsaken till hjärnmetastering. Ungefär 20-40% av bröstcancer patienterna utvecklar någon form av CNS-metastasering. Bröstcancern kan delas in i tre olika subtyper; HER2-positiva, luminala och trippelnegativa. Studier har visat en förlängd överlevnad främst hos subtypen HER2-positiva patienter. Syfte: Att belysa förekomsten av CNS-metastaser bland bröstcancerpatienterna på onkologikliniken i Uppsala sedan 2009-2013, samt att göra en praktisk indelning av patienterna med CNS-spridning beroende av tumörtyp och spridningsmönster av metastaserna samt få en överblick av vilka behandlingar som givits och effekten av dessa. Material och metoder: En retrospektiv kohortstudie baserad på patientdatabas och granskning av patientjournaler för tiden 2009-2013. Materialet bestod av 48 patienter med diagnostiserade CNS-metastaser. Genom onkologiklinikens behandlingsdatabas RealQ® identifierades patienterna. Kompletterande information hämtades från journalgranskning i Cosmic. Patienterna följdes upp efter diagnosen fram till april 2014. Resultat: 33 av de 48 patienterna (83 %) hade strålbehandlats, varav 3 av dessa 33 patienter (4 %) strålbehandlats med boost. 4 av 48 patienter (8 %) opererades i kombination med strålbehandling.  2 patienter (4 %) hade stereotaktiskt strålbehandlats och 9 patienter (19 %) fick inte någon behandling. Genomsnittlig ålder i studiepopulationen var 55 år. Medianen var 56. Högsta ålder var 80 år och lägsta ålder var 34 år. 8 patienter (17 %) utav totala populationen som bestod av 48 patienter överlevde, resterande 40 patienter (83 %) avled. Primärtumör subtyper bland studiepopulationen var (24 %) HER2, (40 %) Luminal och (38 %) trippelnegativ. Det hittades en signifikant skillnad för en längre överlevnad från första metastasen (p=0,001) och från CNS-metastasen (p=0,04). Däremot hittades inte någon signifikant överlevnads skillnad från CNS-metastasen och meningeal metastasen (p=0,11). Dessvärre hade patienterna med meningal metastasen en kortare överlevnad. Konklusion: HER2 och trippelnegativa subtyperna var de vanligaste subtyperna inom studiepopulationen. Patienterna med HER2 positiva subtypen hade en bättre överlevnad i jämförelse med de andra två subtyperna. Detta kan sannolikt förklaras av att mer effektiva läkemedelsbehandlingar är tillgängliga för patienter med denna subtyp. Förklaringen till detta måste vara skadad blodhjärnbarriär vid hjärnmetastasering då dessa läkemedel normalt ej passerar blodhjärnbarriären

  • 189.
    Al-kaisy, Muhammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nilsson, Matthias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Persson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Petterson Bergstrand, Madeleine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sterby, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Vall, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wang, Pin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    En förstudie för framtagning av HIV-proteashämmare: Me-too läkemedel till indinavir2012Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Syftet med denna rapport är att ta fram analoger till indinavir som binder bra till HIV-Iproteaset, wild-type och mutationer. Dessa analoger ska sedan kunna testas experimentelltmed enzymassay och cellbaserad β-galaktosidas aktivitetsassay för att se om de har potentialatt bli nya proteashämmare mot HIV. 80 analoger som tillhandahölls från företagetanlyserades med hjälp av datorsimuleringar för att ta reda på vilka strukturelement som bidrartill bra respektive dålig bindning till HIV-I proteaset och några av de lämpligaste mutationerna.Utifrån resultatet från datoranalysen kunde 48 nya analoger tas fram och även dessaanalyserades med olika beräkningsmoduler. De 30 analogerna med bäst inbindning till wildtypeproteaset och mutationerna valdes ut och rankades. Alla utom en av dessa analoger hadebättre inbindning till proteaset än Indinavir.

  • 190.
    Alm, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Proteomic Characterization of Induced Developmental Neurotoxicity2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The developing brain goes through a number of developmental periods during which it displays an increased sensitivity to exogenous disturbances. On such period is the so called “Brain growth spurt” (BGS) which in humans takes place starting from the third trimester of pregnancy and throughout the first few years of life. The corresponding period in rats and mice is the first postnatal weeks. Exposure to relatively modest concentrations of the brominated flame retardant PBDE-99 during the second week of life in mice causes a more or less permanent impairment in the ability of the animals to adjust properly to environmental changes at adulthood. This “late response on early exposure” reflects the long-term consequences of disrupting the developing brain during a sensitive time period.

    The cellular mechanisms underlying the behavioral effects are far from clear. To address the initial damage occurring around the time of exposure, the approach used in this thesis is to use proteomics to analyze the effects of PBDE-99 on protein expression soon (24 hours) after exposure of the neonatal mouse on postnatal day (PND) 10.The thesis comprises the effects on the proteome in three distinct brain parts: cerebral cortex, striatum and the hippocampus. In addition, an in vitro model was developed and used to evaluate the PBDE-99 effects on cultured cerebral cortex cells from embryonic rat brains.

    Gel-based proteomics (2D-DIGE) coupled to MALDI- or ESI-MS has been used throughout for the proteomics experiments, but other techniques aimed at analyzing both proteins and mRNA have also been used to better characterize the effects.

    Even if the protein complements expressed by the different brain parts and separated with 2D-DIGE are seemingly similar, the effects are apparently specific for the different brain regions. In hippocampus, PBDE induces effects on proteins involved in metabolism and energy production, while the effects in striatum point towards effects on neuroplasticity.

    PBDE-99 changes the expression of cytoskeletal proteins in the cerebral cortex 24 hours after exposure. Interestingly, in vitro exposure of cerebral cortex cells to a PBDE-99 concentration in the same order of magnitude as in the in vivo neonatal brain also induces cytoskeletal effects, in the absence of cytotoxicity. This may suggest effects on regulatory aspects of cytoskeletal dynamics such as those involved in neurite sprouting.

    This thesis also addresses the problems involved in presenting proteomics data. Many of the available methods and approaches for presenting transcriptomics data are not suitable for isoform rich protein data. Modifications of existing methods and the development of a new approach (DEPPS) is also presented. Most importantly, the thesis presents the application and usefulness of proteomics as hypothesis generating techniques in neurotoxicology.

  • 191. Alm, Henrik
    et al.
    Kultima, Kim
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Scholz, Birger
    Nilsson, Anna
    Andrén, Per
    Dencker, Lennart
    Stigson, Michael
    Exposure to brominated flame retardant PBDE-99 affects expression levels of cytoskeletal proteins in neonatal mouse cortexManuskript (Övrigt vetenskapligt)
  • 192.
    Alm, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Scholz, Birger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Nilsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Andrén, Per E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Fex-Svenningsen, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Dencker, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Stigson, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex2008Ingår i: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 29, nr 4, s. 628-637Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.

  • 193.
    Alm, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Scholz, Birger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Fischer, Celia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Viberg, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Eriksson, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Dencker, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Stigson, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Proteomic evaluation of neonatal exposure to 2,2,4,4,5-pentabromodiphenyl ether2006Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 114, nr 2, s. 254-259Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure to the brominated flame retardant 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus. A single oral dose of PBDE-99 (12 mg/kg body weight) or vehicle was administered to male NMRI mice on neonatal day 10, and the striatum and the hippocampus were isolated. Using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE), we found 40 and 56 protein spots with significantly (p < 0.01) altered levels in the striatum and the hippocampus, respectively. We used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to determine the protein identity of 11 spots from the striatum and 10 from the hippocampus. We found that the levels of proteins involved in neurodegeneration and neuroplasticity (e.g., Gap-43/neuromodulin, stathmin) were typically altered in the striatum, and proteins involved in metabolism and energy production [e.g., alpha-enolase; gamma-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, beta subunit (Atp5b); and alpha-synuclein] were typically altered in the hippocampus. Interestingly, many of the identified proteins have been linked to protein kinase C signaling. In conclusion, we identify responses to early exposure to PBDE-99 that could contribute to persistent neurotoxic effects. This study also shows the usefulness of proteomics to identify potential biomarkers of developmental neurotoxicity of organohalogen compounds.

  • 194.
    Alm, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Scholz, Birger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nilsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Andrén, Per E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Savitski, Mikhail M
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Bergman, Åke
    Stigson, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Fex-Svenningsen, Åsa
    Institute of Medical Biology, Anatomy and Neurobiology, University of Southern Denmark, Denmark.
    Dencker, Lennart
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    In Vitro Neurotoxicity of PBDE-99: Immediate and Concentration-Dependent Effects on Protein Expression in Cerebral Cortex Cells2010Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 9, nr 3, s. 1226-1235Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) are commonly used flame retardants in various consumer products. Pre- and postnatal exposure to congeners of PBDEs disrupts normal brain development in rodents. Two-dimensional difference gel electrophoresis (2D-DIGE) was used to analyze concentration-dependent differences in protein expression in cultured cortical cells isolated from rat fetuses (GD 21) after 24 h exposure to PBDE-99 (3, 10, or 30 muM). Changes on a post-translational level were studied using a 1 h exposure to 30 muM PBDE-99. The effects of 24 h exposure to 3 and 30 muM PBDE-99 on mRNA levels were measured using oligonucleotide microarrays. A total of 62, 46, and 443 proteins were differentially expressed compared to controls after 24 h of exposure to 3, 10, and 30 muM PDBE-99, respectively. Of these, 48, 43, and 238 proteins were successfully identified, respectively. We propose that the biological effects of low-concentration PBDE-99 exposure are fundamentally different than effects of high-concentration exposure. Low-dose PBDE-99 exposure induced marked effects on cytoskeletal proteins, which was not correlated to cytotoxicity or major morphological effects, suggesting that other more regulatory aspects of cytoskeletal functions may be affected. Interestingly, 0.3 and 3 muM, but not 10 or 30 muM increased the expression of phosphorylated (active) Gap43, perhaps reflecting effects on neurite extension processes.

  • 195. Almeida, M