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  • 1.
    Abd El-Wahed, Aida A.
    et al.
    Agr Res Ctr, Plant Protect Res Inst, Dept Bee Res, Giza 12627, Egypt..
    Farag, Mohamed A.
    Cairo Univ, Coll Pharm, Pharmacognosy Dept, Kasr El Aini St, Cairo 11562, Egypt.;Amer Univ Cairo, Sch Sci & Engn, Dept Chem, New Cairo 11835, Egypt..
    Eraqi, Walaa A.
    Cairo Univ, Fac Pharm, Dept Microbiol & Immunol, Cairo 11562, Egypt..
    Mersal, Gaber A. M.
    Taif Univ, Coll Sci, Chem Dept, At Taif 21944, Saudi Arabia..
    Zhao, Chao
    Fujian Agr & Forestry Univ, Coll Food Sci, Fuzhou 350002, Fujian, Peoples R China..
    Khalifa, Shaden A. M.
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden..
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm 32512, Egypt.;Jiangsu Univ, Int Res Ctr Food Nutr & Safety, Zhenjiang 212013, Jiangsu, Peoples R China..
    Unravelling the beehive air volatiles profile as analysed via solid-phase microextraction (SPME) and chemometrics2021In: JOURNAL OF KING SAUD UNIVERSITY SCIENCE, ISSN 1018-3647, Vol. 33, no 5, article id 101449Article in journal (Refereed)
    Abstract [en]

    Objective: Beehive air therapy is recognized as a potential remedy for treating asthma, bronchitis, lung fibrosis, and respiratory tract infections. Developed countries in which beehive air therapy is currently authorized include Germany, Hungary, Slovenia, and Austria. However, scientific proof of its efficacy is lacking which warrants further chemical and biological analyses as a proof of concept. In this study, bee-hive air volatile profile was determined for the first time along with its individual components (bees, venom, honey, and beeswax).

    Methods: Volatile compounds were collected from beehive air using solid phase micro-extraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS). Antimicrobial assay of the air released from 4 beehive products was further performed against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and multi drug-resistant Staphylococcus aureus (MRSA) using the in vitro agar-well diffusion and microtiter plate assays.

    Results and conclusions: A total of 56 volatile compounds were identified from beehive air, venom, bee insect and wax air including 6 fatty acids, 6 alcohols, 10 aldehydes, 5 esters, 1 ether, 9 hydrocarbons, 1 phenol, 7 ketones, 1 nitrogenous compound and 10 terpenes. The most abundant constituents were short-chain fatty acids (26.32%) while the lowest were the nitrogenous compounds (0.82%). The principal component analysis (PCA) scores plot of the UPLC/MS dataset showed the similarity of the beehive air to the insect bee's aroma profile. With regards to antimicrobial assay, beehive air and venom exerted the strongest antimicrobial activity among the examined bee products against S. aureus, K. pneumoniae, A. baumannii, and MRSA in agar-well diffusion assay but failing to exert an effect using microtiter plate assay as in case of bee venom against the aforementioned bacteria.

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  • 2.
    Abdel-Moneim, Ahmed S.
    et al.
    Taif Univ, Dept Microbiol, Coll Med, Al Taif 21944, Saudi Arabia; Beni Suef Univ, Fac Vet Med, Dept Virol, Bani Suwayf 62511, Egypt.
    Moore, Matthew D.
    Univ Massachusetts, Dept Food Sci, Amherst, MA 01003 USA.
    Naguib, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Anim Hlth Res Inst, Natl Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt.
    Romalde, Jesus L.
    Univ Santiago de Compostela, CIBUS Fac Biol, Dept Microbiol & Parasitol, Santiago De Compostela 15782, Spain.
    Söderlund-Venermo, Maria
    Univ Helsinki, Dept Virol, Helsinki 00014, Finland.
    WSV 2019: The First Committee Meeting of the World Society for Virology2020In: Virologica Sinica, ISSN 1674-0769, E-ISSN 1995-820X, Vol. 35, no 2, p. 248-252Article in journal (Other academic)
    Abstract [en]

    The World Society for Virology (WSV) was founded and incorporated as a nonprofit organization in the United States in 2017. WSV seeks to strengthen and support both virological research and virologists who conduct research of viruses that affect humans, other animals, plants, and other organisms. One of the objectives of WSV is to connect virologists worldwide and support collaboration. Fulfilling this objective, virologists from fourteen countries in North America, Europe, Africa, Asia, and the Middle East met on 25-27th August 2019 in Stockholm, Sweden at the Karolinska University Hospital for the first Committee Meeting of WSV. This meeting included compelling keynote and honorary speeches and a series of 18 scientific talks were given encompassing a diverse array of subjects within virology. Followed by the scientific session, a business session was held where multiple aspects and next steps of the society were discussed and charted out.

  • 3.
    Abdelwahab, Mahmoud Tareq
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Court, Richard
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Everitt, Daniel
    Global Alliance TB Drug Dev, New York, NY USA..
    Diacon, Andreas H.
    Stellenbosch Univ, Dept Med, Tygerberg, South Africa.;Task Appl Sci, Bellville, South Africa..
    Dawson, Rodney
    Univ Cape Town, Div Pulmonol, Lung Inst, Cape Town, South Africa.;Univ Cape Town, Dept Med, Lung Inst, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.;Uppsala Univ, Dept Pharm, Uppsala, Sweden..
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 7, article id e02687-20Article in journal (Refereed)
    Abstract [en]

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

  • 4.
    Abdelwahab, Mahmoud Tareq
    et al.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Wasserman, Sean
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Brust, James C. M.
    Albert Einstein Coll Med, Div Gen Internal Med, New York, NY USA.;Albert Einstein Coll Med, Div Infect Dis, New York, NY USA..
    Gandhi, Neel R.
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA.;Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA.;Emory Univ, Emory Sch Med, Dept Med Infect Dis, Atlanta, GA USA..
    Meintjes, Graeme
    Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Everitt, Daniel
    Global Alliance TB Drug Dev, New York, NY USA..
    Diacon, Andreas
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Dept Med, Cape Town, South Africa..
    Dawson, Rodney
    Univ Cape Town, Lung Inst, Cape Town, South Africa.;Univ Cape Town, Div Pulmonol, Dept Med, Cape Town, South Africa..
    Wiesner, Lubbe
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Pharm, Med Ctr, Nijmegen, Netherlands.
    Maartens, Gary
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa..
    Denti, Paolo
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Clofazimine pharmacokinetics in patients with TB: dosing implications2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 11, p. 3269-3277Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    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.

  • 6.
    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

  • 7.
    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. 

  • 8.
    Abrantes, João A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data2019In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, no 6, p. 1326-1336Article in journal (Refereed)
    Abstract [en]

    AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.

    METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.

    RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.

    CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.

  • 9.
    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.

  • 10.
    Abrantes, João A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Solms, Alexander
    Bayer, Berlin, Germany.
    Garmann, Dirk
    Bayer, Wuppertal, Germany.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII2019In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 8, no 12, p. 894-903Article in journal (Refereed)
    Abstract [en]

    Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic‐repeated time‐to‐event model‐based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65–0.69), 0.78 (95% CI, 0.76–0.80), and 0.79 (95% CI, 0.77–0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.

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  • 11.
    Abrantes, João
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Solms, Alexander
    Bayer, Berlin, Germany.
    Garmann, Dirk
    Bayer, Wuppertal, Germany.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patientsIn: Article in journal (Refereed)
  • 12. 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.

  • 13.
    Abulfathi, Ahmed A.
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Assawasuwannakit, Piyanan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Donald, Peter R.
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Paediat & Child Hlth, Desmond Tutu TB Ctr, Cape Town, South Africa..
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa..
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens2020In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 76, no 11, p. 1557-1565Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 14.
    Abulfathi, Ahmed A.
    et al.
    Univ Florida, Ctr Pharmacometr & Syst Pharmacol, Dept Pharmaceut, Orlando, FL 32827 USA.;Univ Maiduguri, Coll Med Sci, Dept Clin Pharmacol & Therapeut, Maiduguri, Nigeria.;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Chaba, Linda A.
    Strathmore Univ, Strathmore Inst Math Sci, Nairobi, Kenya..
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands..
    Pillai, Goonaseelan C.
    Univ Cape Town, Fac Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa..
    Rosenkranz, Bernd
    Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.;Fundisa African Acad Med Dev Cape Town, Cape Town, South Africa..
    Pharmacometrics - tools to assure optimal medicine use in low- and middle-income countries: Editorial2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 1034807Article in journal (Other academic)
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  • 15.
    Abulfathi, Ahmed Aliyu
    et al.
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Decloedt, Eric H.
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Svensson, Elin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.
    Diacon, Andreas H.
    Task Appl Sci, Bellville, South Africa;Stellenbosch Univ, Fac Med & Hlth Sci, Dept Med, Cape Town, South Africa.
    Donald, Peter
    Stellenbosch Univ, Fac Med & Hlth Sci, Paediat & Child Hlth & Desmond Tutu TB Ctr, Cape Town, South Africa.
    Reuter, Helmuth
    Stellenbosch Univ, Fac Med & Hlth Sci, Div Clin Pharmacol, Dept Med, POB 241, ZA-8000 Cape Town, South Africa.
    Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis2019In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 58, no 9, p. 1103-1129Article, review/survey (Refereed)
    Abstract [en]

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

  • 16. Adem, Abdu
    et al.
    Madjid, Nather
    Stiedl, Oliver
    Bonito-Oliva, Alessandra
    Konradsson-Geuken, Åsa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Holst, Sarah
    Fisone, Gilberto
    Ögren, Sven Ove
    Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no 5, p. 616-628, article id S0924-977X(19)30195-6Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR) transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA) task in mice and the ability of typical and atypical antipsychotic drugs (APDs) to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg) dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.

  • 17.
    Adjan, V. V.
    et al.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA.
    Hauser, K. F.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, USA.
    Bakalkin, Georgy
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Yakovleva, T.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Gharibyan, A.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Scheff, S. W.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Knapp, P. E.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons2007In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 148, no 3, p. 724-36Article in journal (Refereed)
    Abstract [en]

    Dynorphins are endogenous opioid peptide products of the prodynorphin gene. An extensive literature suggests that dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of dynorphin would protect against tissue damage after spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and prodynorphin(-/-) mice received a moderate contusion injury at 10th thoracic vertebrae (T10). Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post-injury by immunostaining for active caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly, caspase-3 activation was significantly lower in prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that dynorphin A(1-17) was regionally increased in wild-type injured versus sham-injured tissues, although levels of the prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that dynorphin peptides affect the extent of post-injury caspase-3 activation, and that glia are especially sensitive to these effects. By promoting caspase-3 activation, dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that prodynorphin or its peptide products become maladaptive following SCI and contribute to secondary injury.

  • 18. af Klinteberg, Britt
    et al.
    Alm, Per-Olof
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Serotonin, personality and smoking2000Conference paper (Refereed)
  • 19.
    Afroz, Mohasana
    et al.
    Khulna Univ, Life Sci Sch, Pharm Discipline, Khulna, Bangladesh..
    Akter, Sanzida
    Khulna Univ, Life Sci Sch, Pharm Discipline, Khulna, Bangladesh..
    Ahmed, Asif
    Khulna Univ, Life Sci Sch, Biotechnol & Genet Engn Discipline, Khulna, Bangladesh..
    Rouf, Razina
    Bangabandhu Sheikh Mujlbur Rahman Sci & Technol U, Fac Life Sci, Dept Pharm, Gopalgani, Bangladesh..
    Shilpi, Jamil A.
    Khulna Univ, Life Sci Sch, Pharm Discipline, Khulna, Bangladesh..
    Tiralongo, Evelin
    Griffith Univ, Sch Pharm & Pharmacol, Southport, Qld, Australia..
    Sarker, Satyajit D.
    Liverpool John Moores Univ, Ctr Nat Prod Discovery, Sch Pharm & Bimol Sci, Liverpool, Merseyside, England..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Uddin, Shaikh Jamal
    Khulna Univ, Life Sci Sch, Pharm Discipline, Khulna, Bangladesh..
    Ethnobotany and Antimicrobial Peptides From Plants of the Solanaceae Family: An Update and Future Prospects2020In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 11, article id 565Article, review/survey (Refereed)
    Abstract [en]

    The Solanaceae is an important plant family that has been playing an essential role in traditional medicine and human nutrition. Members of the Solanaceae are rich in bioactive metabolites and have been used by different tribes around the world for ages. Antimicrobial peptides (AMPs) from plants have drawn great interest in recent years and raised new hope for developing new antimicrobial agents for meeting the challenges of antibiotic resistance. This review aims to summarize the reported AMPs from plants of the Solanaceae with possible molecular mechanisms of action as well as to correlate their traditional uses with reported antimicrobial actions of the peptides. A systematic literature study was conducted using different databases until August 2019 based on the inclusion and exclusion criteria. According to literature, a variety of AMPs including defensins, protease inhibitor, lectins, thionin-like peptides, vicilin-like peptides, and snaking were isolated from plants of the Solanaceae and were involved in their defense mechanism. These peptides exhibited significant antibacterial, antifungal and antiviral activity against organisms for both plant and human host. Brugmansia, Capsicum, Datura, Nicotiana, Salpichora, Solanum, Petunia, and Withania are the most commonly studied genera for AMPs. Among these genera, Capsicum and the Solanum ranked top according to the total number of studies (35%-38% studies) for different AMPs. The mechanisms of action of the reported AMPs from Solanaceae was not any new rather similar to other reported AMPs including alteration of membrane potential and permeability, membrane pore formation, and cell aggregation. Whereas, induction of cell membrane permiabilization, inhibition of germination and alteration of hyphal growth were reported as mechanisms of antifungal activity. Plants of the Solanaceae have been used traditionally as antimicrobial, insecticidal, and antiinfectious agents, and as poisons. The reported AMPs from the Solanaceae are the products of chemical shields to protect plants from microorganisms and pests which unfold an obvious link with their traditional medicinal use. In summary, it is evident that AMPs from this family possess considerable antimicrobial activity against a wide range of bacterial and fungal pathogens and can be regarded as a potential source for lead molecules to develop new antimicrobial agents.

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  • 20. Agerstrand, Marlene
    et al.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bjorlenius, Berndt
    Breitholtz, Magnus
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fick, Jerker
    Gunnarsson, Lina
    Larsson, D. G. Joakim
    Sumpter, John P.
    Tysklind, Mats
    Ruden, Christina
    Improving Environmental Risk Assessment of Human Pharmaceuticals2015In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 49, no 9, p. 5336-5345Article in journal (Refereed)
    Abstract [en]

    This paper presents 10 recommendations for improving the European Medicines Agency's guidance for environmental risk assessment of human pharmaceutical products. The recommendations are based on up-to-date, available science in combination with experiences from other chemical frameworks such as the REACH-legislation for industrial chemicals. The recommendations concern: expanding the scope of the current guideline; requirements to assess the risk for development of antibiotic resistance; jointly performed assessments; refinement of the test proposal; mixture toxicity assessments on active pharmaceutical ingredients with similar modes of action; use of all available ecotoxicity studies; mandatory reviews; increased transparency; inclusion of emission data from production; and a risk management option. We believe that implementation of our recommendations would strengthen the protection of the environment and be beneficial to society. Legislation and guidance documents need to be updated at regular intervals in order to incorporate new knowledge from the scientific community. This is particularly important for regulatory documents concerning pharmaceuticals in the environment since this is a research field that has been growing substantially in the last decades.

  • 21.
    Agrawal, Mukta
    et al.
    Rungta Coll Pharmaceut Sci & Res, Kohka Kurud Rd, Bhilai , Chhattisgarh, India..
    Ajazuddin, A
    Rungta College of Pharmaceutical Sciences and Research, Kohka-Kurud Road, Bhilai 490024, Chhattisgarh, India.
    Tripathi, Dulal K.
    Rungta Coll Pharmaceut Sci & Res, Kohka Kurud Rd, Bhilai 490024, Chhattisgarh, India..
    Saraf, Swarnlata
    Pt Ravishankar Shukla Univ, Univ Inst Pharm, Raipur 492010, Chhattisgarh, India..
    Saraf, Shailendra
    Pt Ravishankar Shukla Univ, Univ Inst Pharm, Raipur 492010, Chhattisgarh, India..
    Antimisiaris, Sophia G.
    Univ Patras, Dept Pharm, Lab Pharmaceut Technol, Rion 26510, Greece.;Inst Chem Engn, FORTH ICE HT, Patras 25104, Greece..
    Mourtas, Spyridon
    Univ Patras, Dept Pharm, Lab Pharmaceut Technol, Rion 26510, Greece..
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alexander, Amit
    Rungta Coll Pharmaceut Sci & Res, Kohka Kurud Rd, Bhilai 490024, Chhattisgarh, India..
    Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease2017In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 260, p. 61-77Article, review/survey (Refereed)
    Abstract [en]

    In this modern era, with the help of various advanced technologies, medical science has overcome most of the health-related issues successfully. Though, some diseases still remain unresolved due to various physiological barriers. One such condition is Alzheimer; a neurodegenerative disorder characterized by progressive memory impairment, behavioral abnormalities, mood swing and disturbed routine activities of the person suffering from. It is well known to all that the brain is entirely covered by a protective layer commonly known as blood brain barrier (BBB) which is responsible to maintain the homeostasis of brain by restricting the entry of toxic substances, drug molecules, various proteins and peptides, small hydrophilic molecules, large lipophilic substances and so many other peripheral components to protect the brain from any harmful stimuli. This functionally essential structure creates a major hurdle for delivery of any drug into the brain. Still, there are some provisions on BBB which facilitate the entry of useful substances in the brain via specific mechanisms like passive diffusion, receptor-mediated transcytosis, carrier-mediated transcytosis etc. Another important factor for drug transport is the selection of a suitable drug delivery systems like, liposome, which is a novel drug carrier system offering a potential approach to resolving this problem. Its unique phospholipid bilayer structure (similar to physiological membrane) had made it more compatible with the lipoidal layer of BBB and helps the drug to enter the brain. The present review work focused on various surface modifications with functional ligand (like lactoferrin, transferrin etc.) and carrier molecules (such as glutathione, glucose etc.) on the liposomal structure to enhance its brain targeting ability towards the successful treatment of Alzheimer disease.

  • 22.
    Ahmed, Fozia
    et al.
    Inst Savoir Montfort Rech, 1E103,713 Montreal Rd, Ottawa, ON K1K 0T2, Canada; Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Sarsenbayeva, Assel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Aguer, Céline
    Inst Savoir Montfort Rech, 1E103,713 Montreal Rd, Ottawa, ON K1K 0T2, Canada; Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada; Univ Ottawa, Fac Hlth Sci, Sch Human Kinet, Ottawa, ON, Canada; Univ Ottawa, Fac Hlth Sci, Interdisciplinary Sch Hlth Sci, Ottawa, ON, Canada.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    The effects of bisphenol A and bisphenol S on adipokine expression and glucose metabolism in human adipose tissue2020In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 445, article id 152600Article in journal (Refereed)
    Abstract [en]

    Purpose

    The environmental endocrine disruptors, bisphenol A (BPA) and bisphenol S (BPS) are associated with the development of type 2 diabetes. We aim to study the effects of BPA or BPS exposure on adipokine expression in human adipose tissue and on adipocyte glucose uptake.

    Methods

    Human subcutaneous adipose tissue was treated for 24 or 72 h with environmentally-relevant and supraphysiological concentrations of BPA or BPS (1–104 nM). Following exposure, gene expression of proinflammatory cytokines, adipokines, and estrogen receptors was measured in adipose tissue. Glucose uptake and the insulin signalling pathway were analyzed in isolated adipocytes following adipose tissue culture with BPA for 24 h.

    Results

    Adipose tissue treated with BPA for 24 h had reduced expression of the proinflammatory genes (IL6, IL1B, TNFA) and adipokines (ADIPOQ, FABP4). BPA and BPS had no effect on the expression of other proinflammatory genes (IL33), adipokines (LEP), or receptors (ESR1, ESR2) after 72-h exposure. Adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h had reduced insulin-stimulated glucose uptake, without altered gene and protein levels of key insulin signalling pathway markers.

    Conclusions

    We found that human adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h, but not BPS, reduced expression of proinflammatory genes and adipokines. Furthermore, BPA reduced glucose uptake in adipocytes independently of insulin signalling. Such mechanisms can contribute to the development of insulin resistance associated with BPA exposure.

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  • 23.
    Aithal, Guruprasad P.
    et al.
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Nicoletti, Paola
    Columbia Univ, New York, NY USA..
    Bjornsson, Einar
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Lucena, M. I.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Andrade, Raul J.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Grove, Jane
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Stephens, C.
    Univ Malaga, E-29071 Malaga, Spain..
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Utrecht, Netherlands..
    Martin, Jennifer H.
    Univ Queensland, Brisbane, Qld, Australia.;Princess Alexandra Hosp, Brisbane, Qld, Australia..
    Cascorbi, Ingolf
    Univ Hosp Schleswig Holstein, Kiel, Germany..
    Dillon, John F.
    Ninewells Hosp & Med Sch, Dundee, Scotland..
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Larrey, Dominique G.
    Hop St Eloi, Montpellier, France..
    Molokhia, Mariam
    Univ London, Kings Coll London, London SW3 6LX, England..
    Kullak-Ublick, Gerd A.
    Univ Zurich, Zurich, Switzerland..
    Ibanez, Luisa
    Hosp Univ Vall Hebron, Barcelona, Spain..
    Pirmohamed, Munir
    Univ Liverpool, Liverpool L69 3BX, Merseyside, England..
    Qin, Shengying
    Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China..
    Sawle, Ashley
    Columbia Univ, New York, NY USA..
    Bessone, Fernando
    Univ Nacl Rosario, Fac Ciencias Med, RA-2000 Rosario, Argentina..
    Hernandez, Nelia
    Univ Republ, Mentevideo, Uruguay..
    Stolz, Andrew
    Univ So Calif, Los Angeles, CA USA..
    Chalasani, Naga P.
    Indiana Univ, Indianapolis, IN 46204 USA..
    Serrano, Jose
    Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA..
    Barnhart, Huiman X.
    Duke Clin Res Inst, Durham, NC USA..
    Fontana, Robert J.
    Univ Michigan, Ann Arbor, MI 48109 USA..
    Watkins, Paul
    Hamner UNC Inst Drug Safety Sci, Durham, NC USA..
    Urban, Thomas J.
    UNC Eshelman Sch Pharm, Chapel Hill, NC USA..
    Daly, Ann K.
    Newcastle Univ, Newcastle, NSW, Australia..
    HLA-A*33:01 is strongly associated with drug-induced liver injury (DILI) due to terbinafine and several other unrelated compounds2015In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 62, p. 325A-326AArticle in journal (Other academic)
  • 24.
    Akhtar, Evana
    et al.
    Icddr B, Infect Dis Div, Dhaka 1212, Bangladesh.
    Roy, Anjan Kumar
    Icddr B, Infect Dis Div, Dhaka 1212, Bangladesh.
    Haq, Md Ahsanul
    Icddr B, Infect Dis Div, Dhaka 1212, Bangladesh.
    von Ehrenstein, Ondine S.
    Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Community Hlth Sci & Epidemiol, Los Angeles, CA 90024 USA.
    Ahmed, Sultan
    Icddr B, Infect Dis Div, Dhaka 1212, Bangladesh.
    Vahter, Marie
    Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden.
    Ekström, Eva-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Kippler, Maria
    Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden.
    Wagatsuma, Yukiko
    Univ Tsukuba, Fac Med, Dept Clin Trial & Clin Epidemiol, Tsukuba, Ibaraki, Japan.
    Raqib, Rubhana
    Icddr B, Infect Dis Div, Dhaka 1212, Bangladesh.
    A longitudinal study of rural Bangladeshi children with long-term arsenic and cadmium exposures and biomarkers of cardiometabolic diseases2021In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 271, article id 116333Article in journal (Refereed)
    Abstract [en]

    There is growing interest in understanding the contribution of environmental toxicant exposure in early life to development of cardiometabolic diseases (CMD) in adulthood. We aimed to assess associations of early life exposure to arsenic and cadmium with biomarkers of CMD in children in rural Bangladesh. From a longitudinal mother-child cohort in Matlab, Bangladesh, we followed up 540 pairs. Exposure to arsenic (U–As) and cadmium (U–Cd) was assessed by concentrations in urine from mothers at gestational week 8 (GW8) and children at ages 4.5 and 9 years. Blood pressure and anthropometric indices were measured at 4.5 and 9 years. Metabolic markers (lipids, glucose, hemoglobin A1c, adipokines, estimated glomerular filtration rate (eGFR) were determined in plasma/blood of 9 years old children. In linear regression models, adjusted for child sex, age, height-for-age z score (HAZ), BMI-for-age z score (BAZ), socioeconomic status (SES) and maternal education, each doubling of maternal and early childhood U–Cd was associated with 0.73 and 0.82 mmHg increase in systolic blood pressure (SBP) respectively. Both early and concurrent childhood U–Cd was associated with diastolic (D)BP (β = 0.80 at 4.5 years; β = 0.75 at 9 years). Each doubling of U–Cd at 9 years was associated with decrements of 4.98 mg/dL of total cholesterol (TC), 1.75 mg/dL high-density lipoprotein (HDL), 3.85 mg/dL low-density lipoprotein (LDL), 0.43 mg/dL glucose and 4.29 units eGFR. Each doubling of maternal U–Cd was associated with a decrement of 1.23 mg/dL HDL. Both maternal and childhood U–As were associated with decrement in TC and HDL. Multiple comparisons were checked with family-wise error rate Bonferroni-type-approach. The negative associations of arsenic and cadmium with biomarkers of CMD in preadolescent children indicated influence of both metal(loid)s on fat and carbohydrate metabolism, while cadmium additionally influenced kidney function and BP. Thus, fewer outcomes were associated with U–As compared to U–Cd at preadolescence.

  • 25. Akkermann, Kirsti
    et al.
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    Serotonin transporter gene promoter polymorphism affects the severity of binge eating in general population2010In: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 34, no 1, p. 111-114Article, review/survey (Refereed)
    Abstract [en]

    Objective: The s-allele of the 5-HTTLPR has been suggested to lead to the development of less efficient and less flexible 5-HT system and has been associated to different forms of psychopathology. It has also been shown that alterations in serotonergic activity contribute to the pathophysiology of binge eating but it is not clear which changes in 5-HT function observed in eating disorder patients represent trait vs state effect. We investigated the association between the 5-HTTLPR and binge eating in a population-representative sample of women, and tested whether the 5-HTTLPR genotype influences the severity of binge eating. Methods: The sample was based on women participating in the third wave of the Estonian Children Personality, Behaviour and Health Study. EDI-2 subscales - drive for thinness and bulimia - were used to assess eating behaviour and attitudes. Barratt Impulsiveness Scale (BIS-11) and State and Trait Anxiety Inventory (STAI) were used to measure impulsivity and anxiety. Participants were genotyped for the 5-HTTLPR. Results: There was no 5-HTTLPR genotype effect on binge eating even after the covarying effect of impulsivity and anxiety was controlled for. However, women prone to binge eating and carrying the s-allele showed significantly higher levels of bulimia scores, and among them, women with s/s genotype had also higher levels of state anxiety and tendency for higher impulsivity. Conclusions: While the 5-HTTLPR genotype does not predict symptoms of eating disorder in general population, the s-allele, and especially the s/s genotype increases the risk for affective instability and symptom severity.

  • 26.
    Al Asadi, Mona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Botulinumtoxin: För- och emot dess användning i skönhetsbranschen2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Botulinumtoxin: För och emot dess användning i skönhetsbranschen

    Bakgrund: Botulinumtoxin (BTX) är ett kraftfullt neurotoxin som produceras av den grampositiva och anaeroba bakterien Clostridium botulinum. BTX används i medicinskt syfte vid behandling av till exempel kronisk migrän, spasticitet efter stroke, och urinläckage vid nervskada. Utöver det används BTX inom skönhetsbranschens som då injiceras i mycket låga doser under huden i muskler för att minska rynkor i olika ansiktsregioner

    Syfte: Användningen och lämpligheten inom skönhetsbranschen har ifrågasatts , och syftet med detta arbeta har därför varit att utvärdera och ta ställning till om BTX fortsättningsvis bör användas i kosmetiskt syfte.

    Metod: Litteraturstudie där vetenskapliga artiklar söktes i databasen PubMed med kombinationer av sökord, artiklar som sedan kunde användas för att besvara den aktuella frågeställningen.

    Resultat: Olika studier har visats att BTX är ett effektivt och säkert toxin vid skönhetsbehandling, men flera studier visade också att BTX-relaterade biverkningar uppkom efter skönhetsbehandling.

    Slutsats: BTX bör inte fortsätta användas för skönhetsbehandling trots positiva effekter mot rynkor i ansiktet som visades i studierna. Injektion med BTX kan bidra till att kunder i skönhetssalonger blir svårbedömda patienter vid besök hos läkare i primärvården som inte förstår att de problem patienten söker för beror på BTX-inducerade biverkningar efter skönhetsbehandling med BTX.

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  • 27.
    Al Shemaili, Jasem
    et al.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Parekh, Khatija A.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Newman, Robert A.
    Phoenix Biotechnol Inc, San Antonio, TX 78217 USA..
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Woodward, Carl
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adem, Abdu
    United Arab Emirates Univ, Dept Pharmacol, Fac Med, POB 17666, Al Ain, U Arab Emirates..
    Collin, Peter
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adrian, Thomas E.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer2016In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, no 6, article id 115Article in journal (Refereed)
    Abstract [en]

    The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

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  • 28.
    Alajlani, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Karl Franzens Univ Graz, Inst Pharmaceut Sci, Dept Pharmacognosy, Univ Pl 4, A-8010 Graz, Austria..
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Predicting the mechanism of action of antituberculosis agents using chemical global positioning system - natural product2016In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Article in journal (Other academic)
  • 29.
    Alarcon, Sonia
    et al.
    Univ Miguel Hernandez Elche, Inst Bioingn, Elche, Alicante, Spain.;Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Esteban, Javier
    Univ Miguel Hernandez Elche, Inst Bioingn, Elche, Alicante, Spain.
    Roos, Robert
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.;Grand Duchy Luxembourg, Lab & Mine Inspect, Minist Work, Luxembourg, Luxembourg.
    Heikkinen, Paivi
    Finnish Inst Hlth & Welf THL, Environm Hlth Unit, POB 95, FI-70701 Kuopio, Finland.
    Sanchez-Perez, Ismael
    Univ Miguel Hernandez Elche, Inst Bioingn, Elche, Alicante, Spain.
    Adamsson, Annika
    Univ Turku, Turku Univ Hosp, Inst Biomed, Dept Paediat,Res Ctr Integrat Physiol & Pharmac, FI-20520 Turku, Finland.;Univ Turku, Turku Univ Hosp, Inst Biomed, Dept Paediat,Ctr Populat Hlth Res, FI-20520 Turku, Finland.
    Toppari, Jorma
    Univ Turku, Turku Univ Hosp, Inst Biomed, Dept Paediat,Res Ctr Integrat Physiol & Pharmac, FI-20520 Turku, Finland.;Univ Turku, Turku Univ Hosp, Inst Biomed, Dept Paediat,Ctr Populat Hlth Res, FI-20520 Turku, Finland.
    Koskela, Antti
    Univ Oulu, Inst Canc Res & Translat Med, Dept Anat & Cell Biol, Oulu, Finland.
    Finnila, Mikko A. J.
    Univ Oulu, Fac Med, Res Unit Med Imaging Phys & Technol, Oulu, Finland.
    Tuukkanen, Juha
    Univ Oulu, Inst Canc Res & Translat Med, Dept Anat & Cell Biol, Oulu, Finland.
    Herlin, Maria
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Hamscher, Gerd
    Justus Liebig Univ, Inst Food Chem & Food Biotechnol, D-35392 Giessen, Germany.
    Leslie, Heather A.
    Vrije Univ Amsterdam, Dept Environm & Hlth, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands.
    Korkalainen, Merja
    Finnish Inst Hlth & Welf THL, Environm Hlth Unit, POB 95, FI-70701 Kuopio, Finland.
    Halldin, Krister
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Schrenk, Dieter
    Univ Kaiserslautern, Food Chem & Toxicol, D-67663 Kaiserslautern, Germany.
    Hakansson, Helen
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Viluksela, Matti
    Univ Eastern Finland, Sch Pharm Toxicol, Dept Environm & Biol Sci, Kuopio, Finland.;Uppsala Univ, BMC, Off Med & Pharm, SE-75123 Uppsala, Sweden.
    Endocrine, metabolic and apical effects of in utero and lactational exposure to non-dioxin-like 2,2 ',3,4,4 ',5,5 '-heptachlorobiphenyl (PCB 180): A postnatal follow-up study in rats2021In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 102, p. 109-127Article in journal (Refereed)
    Abstract [en]

    PCB 180 is a persistent and abundant non-dioxin-like PCB (NDL-PCB). We determined the developmental toxicity profile of ultrapure PCB 180 in developing offspring following in utero and lactational exposure with the focus on endocrine, metabolic and retinoid system alterations. Pregnant rats were given total doses of 0, 10, 30, 100, 300 or 1000 mg PCB 180/kg bw on gestational days 7-10 by oral gavage, and the offspring were sampled on postnatal days (PND) 7, 35 and 84. Decreased serum testosterone and triiodothyronine concentrations on PND 84, altered liver retinoid levels, increased liver weights and induced 7-pentoxyresorufin O-dealkylase (PROD) activity were the sensitive effects used for margin of exposure (MoE) calculations. Liver weights were increased together with induction of the metabolizing enzymes cytochrome P450 (CYP) 2B1, CYP3A1, and CYP1A1. Less sensitive effects included decreased serum estradiol and increased luteinizing hormone levels in females, decreased prostate and seminal vesicle weight and increased pituitary weight in males, increased cortical bone area and thickness of tibial diaphysis in females and decreased cortical bone mineral density in males. Developmental toxicity profiles were partly different in male and female offspring, males being more sensitive to increased liver weight, PROD induction and decreased thyroxine concentrations. MoE assessment indicated that the 95th percentile of current maternal PCB 180 concentrations do not exceed the estimated tolerable human lipid-based PCB 180 concentration. Although PCB 180 is much less potent than dioxin-like compounds, it shares several toxicological targets suggesting a potential for interactions.

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  • 30.
    Alavian-Ghavanini, Ali
    et al.
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Lin, Ping-I
    Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rimfors, Sabina Risen
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Tang, Mandy
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lindh, Christian
    Lund Univ, Div Occupat & Environm Med, S-22185 Lund, Sweden.
    Bornehag, Carl-Gustaf
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA;Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Rueegg, Joelle
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 11315Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, Iow APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and Iow APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.

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  • 31.
    Alexander, Stephen P. H.
    et al.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Christopoulos, Arthur
    Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia.;Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia..
    Davenport, Anthony P.
    Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England..
    Kelly, Eamonn
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Mathie, Alistair A.
    Univ Suffolk, Sch EAST Engn Arts Sci & Technol, Ipswich IP4 1QJ, Suffolk, England..
    Peters, John A.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Educ Inst, Neurosci Div, Dundee DD1 9SY, Angus, Scotland..
    Veale, Emma L.
    Univ Greenwich, Medway Sch Pharm, Anson Bldg,Cent Ave, Chatham ME4 4TB, Kent, England.;Univ Kent, Medway, Anson Bldg,Cent Ave, Chatham ME4 4TB, Kent, England..
    Armstrong, Jane F.
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Faccenda, Elena
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Harding, Simon D.
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Davies, Jamie A.
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Abbracchio, Maria Pia
    Univ Milan, Milan, Italy..
    Abraham, George
    Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England..
    Agoulnik, Alexander
    Florida Int Univ, Miami, FL 33199 USA..
    Alexander, Wayne
    Emory Univ, Atlanta, GA 30322 USA..
    Al-hosaini, Khaled
    King Saud Univ, Riyadh, Saudi Arabia..
    Baeck, Magnus
    Karolinska Univ Hosp, Stockholm, Sweden..
    Baker, Jillian G.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Barnes, Nicholas M.
    Univ Birmingham, Birmingham, Warwickshire, England..
    Bathgate, Ross
    Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia..
    Beaulieu, Jean-Martin
    Univ Toronto, Toronto, ON, Canada..
    Beck-Sickinger, Annette G.
    Univ Leipzig, Leipzig, Germany..
    Behrens, Maik
    Tech Univ Munich, Freising Weihenstephan, Germany..
    Bernstein, Kenneth E.
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Bettler, Bernhard
    Univ Basel, Basel, Switzerland..
    Birdsall, Nigel J. M.
    Francis Crick Inst, London, England..
    Blaho, Victoria
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Boulay, Francois
    Univ Grenoble Alpes, Grenoble, France..
    Bousquet, Corinne
    French Inst Hlth & Med Res INSERM, Toulouse, France..
    Braeuner-Osborne, Hans
    Univ Copenhagen, Copenhagen, Denmark..
    Burnstock, Geoffrey
    UCL, London, England..
    Calo, Girolamo
    Univ Padua, Padua, Italy..
    Castano, Justo P.
    Univ Cordoba, Cordoba, Spain..
    Catt, Kevin J.
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Ceruti, Stefania
    Univ Milan, Milan, Italy..
    Chazot, Paul
    Univ Durham, Durham, England..
    Chiang, Nan
    Harvard Univ, Boston, MA 02115 USA..
    Chini, Bice
    Univ Milano Bicocca, Vedano Al Lambro, Italy..
    Chun, Jerold
    Univ Calif San Diego, La Jolla, CA 92093 USA..
    Cianciulli, Antonia
    Univ Bari, Bari, Italy..
    Civelli, Olivier
    Univ Calif Irvine, Irvine, CA USA..
    Clapp, Lucie H.
    UCL, London, England..
    Couture, Rejean
    Univ Montreal, Montreal, PQ, Canada..
    Cox, Helen M.
    Kings Coll London, London, England..
    Csaba, Zsolt
    French Inst Hlth & Med Res INSERM, Paris, France..
    Dahlgren, Claes
    Univ Gothenburg, Gothenburg, Sweden..
    Dent, Gordon
    Keele Univ, Keele, Staffs, England..
    Douglas, Steven D.
    Univ Penn, Philadelphia, PA 19104 USA..
    Dournaud, Pascal
    French Inst Hlth & Med Res INSERM, Paris, France..
    Eguchi, Satoru
    Temple Univ, Philadelphia, PA 19122 USA..
    Escher, Emanuel
    Univ Sherbrooke, Sherbrooke, PQ, Canada..
    Filardo, Edward J.
    Univ Iowa, Iowa City, IA USA..
    Fong, Tung
    Labcorp Drug Dev, Somerset, NJ USA..
    Fumagalli, Marta
    Univ Milan, Milan, Italy..
    Gainetdinov, Raul R.
    St Petersburg State Univ, St Petersburg, Russia..
    Garelja, Michael L.
    Univ Otago, Dunedin, New Zealand..
    de Gasparo, Marc
    MG Consulting Co, Basel, Switzerland..
    Gerard, Craig
    Harvard Univ, Boston, MA 02115 USA..
    Gershengorn, Marvin
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Gobeil, Fernand
    Univ Sherbrooke, Sherbrooke, PQ, Canada..
    Goodfriend, Theodore L.
    Univ Wisconsin, Madison, WI USA..
    Goudet, Cyril
    French Natl Ctr Sci Res, Montpellier, France..
    Graetz, Lukas
    Karolinska Inst, Stockholm, Sweden..
    Gregory, Karen J.
    Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia.;Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia..
    Gundlach, Andrew L.
    Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia..
    Hamann, Joerg
    Univ Amsterdam, Amsterdam, Netherlands..
    Hanson, Julien
    Univ Liege, Liege, Belgium..
    Hauger, Richard L.
    Univ Calif San Diego, La Jolla, CA 92093 USA..
    Hay, Debbie L.
    Univ Otago, Dunedin, New Zealand..
    Heinemann, Akos
    Med Univ Graz, Graz, Austria..
    Herr, Deron
    San Diego State Univ, San Diego, CA 92182 USA..
    Hollenberg, Morley D.
    Univ Calgary, Calgary, AB, Canada..
    Holliday, Nicholas D.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Horiuchi, Mastgugu
    Ehime Univ, Matsuyama, Ehime, Japan..
    Hoyer, Daniel
    Univ Melbourne, Melbourne, Vic, Australia..
    Hunyady, Laszlo
    Semmelwe Univ, Budapest, Hungary..
    Husain, Ahsan
    Emory Univ, Atlanta, GA 30322 USA..
    Ijzerman, Adriaan P.
    Leiden Univ, Leiden, Netherlands..
    Inagami, Tadashi
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Jacobson, Kenneth A.
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Jensen, Robert T.
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Jockers, Ralf
    French Inst Hlth & Med Res INSERM, Paris, France..
    Jonnalagadda, Deepa
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Karnik, Sadashiva
    Lerner Res Inst, Cleveland, OH USA..
    Kaupmann, Klemens
    Novartis, Basel, Switzerland..
    Kemp, Jacqueline
    Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA..
    Kennedy, Charles
    Strathclyde Univ, Glasgow, Lanark, Scotland..
    Kihara, Yasuyuki
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Kitazawa, Takio
    Rakuno Gakuen Univ, Ebetsu, Hokkaido, Japan..
    Kozielewicz, Pawel
    Karolinska Inst, Stockholm, Sweden..
    Kreienkamp, Hans-Juergen
    Univ Hamburg, Hamburg, Germany..
    Kukkonen, Jyrki P.
    Univ Helsinki, Helsinki, Finland..
    Langenhan, Tobias
    Univ Leipzig, Leipzig, Germany..
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Dan Larhammar. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leach, Katie
    Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia.;Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia..
    Lecca, Davide
    Univ Milan, Milan, Italy..
    Lee, John D.
    Univ Queensland, Brisbane, Qld, Australia..
    Leeman, Susan E.
    Boston Univ, Boston, MA 02215 USA..
    Leprince, Jerome
    Univ Rouen, Rouen, France..
    Li, Xaria X.
    Univ Queensland, Toowoomba, Qld, Australia..
    Lolait, Stephen J.
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Lupp, Amelie
    Friedrich Schiller Univ Jena, Jena, Germany..
    Macrae, Robyn
    Univ Cambridge, Cambridge, England..
    Maguire, Janet
    Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England..
    Malfacini, Davide
    Univ Padua, Padua, Italy..
    Mazella, Jean
    French Natl Ctr Sci Res CNRS, Valbonne, France..
    Mcardle, Craig A.
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Melmed, Shlomo
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Michel, Martin C.
    Johannes Gutenberg Univ Mainz, Mainz, Germany..
    Miller, Laurence J.
    Mayo Fdn Med Educ & Res, Scottsdale, AZ USA..
    Mitolo, Vincenzo
    Univ Bari, Bari, Italy..
    Mouillac, Bernard
    French Natl Ctr Sci Res, Montpellier, France..
    Mueller, Christa E.
    Univ Bonn, Bonn, Germany..
    Murphy, Philip M.
    Edge Hill Univ, Bethesda, MD USA..
    Nahon, Jean-Louis
    French Natl Ctr Sci Res CNRS, Valbonne, France..
    Ngo, Tony
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Norel, Xavier
    French Inst Hlth & Med Res INSERM, Paris, France..
    Nyimanu, Duuamene
    Univ Cambridge, Cambridge, England..
    O'Carroll, Anne-Marie
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Offermanns, Stefan
    Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany..
    Panaro, Maria Antonietta
    Univ Bari, Bari, Italy..
    Parmentier, Marc
    Free Univ Brussels, Brussels, Belgium..
    Pertwee, Roger G.
    Univ Aberdeen, Aberdeen, Scotland..
    Pin, Jean-Philippe
    Univ Montpellier, Montpellier, France..
    Prossnitz, Eric R.
    Univ New Mexico, Albuquerque, NM 87131 USA..
    Quinn, Mark
    Montana State Univ, Bozeman, MT 59717 USA..
    Ramachandran, Rithwik
    Univ Calgary, Calgary, AB, Canada..
    Ray, Manisha
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Reinscheid, Rainer K.
    Friedrich Schiller Univ Jena, Jena, Germany..
    Rondard, Philippe
    Univ Montpellier, Montpellier, France..
    Rovati, G. Enrico
    Univ Milan, Milan, Italy..
    Ruzza, Chiara
    Univ Ferrara, Ferrara, Italy..
    Sanger, Gareth J.
    Queen Mary Univ London, London, England..
    Schoeneberg, Torsten
    Univ Leipzig, Leipzig, Germany..
    Schulte, Gunnar
    Karolinska Inst, Stockholm, Sweden..
    Schulz, Stefan
    Friedrich Schiller Univ Jena, Jena, Germany..
    Segaloff, Deborah L.
    Univ Iowa, Iowa City, IA USA..
    Serhan, Charles N.
    Harvard Univ, Boston, MA 02115 USA..
    Singh, Khuraijam Dhanachandra
    Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA..
    Smith, Craig M.
    Deakin Univ, Waurn Ponds, Australia..
    Stoddart, Leigh A.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Sugimoto, Yukihiko
    Kumamoto Univ, Kumamoto, Japan..
    Summers, Roger
    Monash Univ, Melbourne, Vic, Australia..
    Tan, Valerie P.
    Univ Calif San Diego, La Jolla, CA 92093 USA..
    Thal, David
    Monash Univ, Melbourne, Vic, Australia..
    Thomas, Walter ( Wally)
    Univ Queensland, Toowoomba, Qld, Australia..
    Timmermans, Pieter B. M. W. M.
    Kosan Biosci Inc, San Francisco, CA USA..
    Tirupula, Kalyan
    Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA..
    Toll, Lawrence
    Florida Atlantic Univ, Jupiter, FL USA..
    Tulipano, Giovanni
    Univ Brescia, Brescia, Italy..
    Unal, Hamiyet
    Cleveland Clin, Cleveland, OH 44106 USA..
    Unger, Thomas
    Maastricht Univ, Maastricht, Netherlands..
    Valant, Celine
    Monash Univ, Melbourne, Vic, Australia..
    Vanderheyden, Patrick
    Free Univ Brussels, Brussels, Belgium..
    Vaudry, David
    Univ Rouen, Rouen, France..
    Vaudry, Hubert
    Univ Rouen, Rouen, France..
    Vilardaga, Jean-Pierre
    Univ Pittsburgh, Pittsburgh, PA USA..
    Walker, Christopher S.
    Univ Auckland, Auckland, New Zealand..
    Wang, Ji Ming
    NCI, Frederick, MD 21701 USA..
    Ward, Donald T.
    Univ Manchester, Manchester, Lancs, England..
    Wester, Hans-Juergen
    Tech Univ Munich, Munich, Germany..
    Willars, Gary B.
    Univ Leicester, Leicester, Leics, England..
    Williams, Tom Lloyd
    Univ Cambridge, Cambridge, England..
    Woodruff, Trent M.
    Univ Queensland, Toowoomba, Qld, Australia..
    Yao, Chengcan
    Univ Edinburgh, Edinburgh, Midlothian, Scotland..
    Ye, Richard D.
    Chinese Univ Hong Kong, Shenzhen, Hong Kong, Peoples R China..
    The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors2023In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 180, no Suppl. 2, p. S23-S144Article in journal (Refereed)
    Abstract [en]

    The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

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  • 32.
    Alffenaar, J. W. C.
    et al.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.
    Stocker, S. L.
    Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;St Vincents Hosp, Dept Clin Pharmacol & Toxicol, Sydney, NSW, Australia.;Univ NSW, St Vincents Clin Campus, Kensington, NSW, Australia.
    Forsman, L. Davies
    Karolinska Inst, Dept Med, Div Infect Dis, Solna, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Solna, Sweden.
    Garcia-Prats, A.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa.;Univ Wisconsin, Dept Pediat, Madison, WI USA.
    Heysell, S. K.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA.
    Aarnoutse, R. E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Nijmegen, Netherlands.
    Akkerman, O. W.
    Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis & TB, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, TB Ctr Beatrixoord, Haren, Netherlands.
    Aleksa, A.
    Grodno State Med Univ, Educ Inst, Grodno, BELARUS.
    van Altena, R.
    Asian Harm Reduct Network AHRN, Yangon, Myanmar.;Med Act Myanmar MAM, Yangon, Myanmar.
    de Onata, W. Arrazola
    Belgian Sci Inst Publ Hlth, Belgian Lung & TB Assoc, Brussels, Belgium.
    Bhavani, P. K.
    Indian Council Med Res Natl Inst Res TB, Int Ctr Excellence Res, Chennai, Tamil Nadu, India.
    Van't Boveneind-Vrubleuskaya, N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.;Metropolitan Publ Hlth Serv, Dept Publ Hlth TB Control, The Hague, Netherlands.
    Carvalho, A. C. C.
    Fundacao Oswaldo Cruz, Lab Inovacoes Terapias Ensino & Bioprod LITEB, Inst Oswaldo Cruz, Rio De Janeiro, RJ, Brazil.
    Centis, R.
    Ist Ricovero & Cura Carattere Sci IRCCS, Ist Clin Sci Maugeri, Serv Epidemiol Clin Malattie Resp, Tradate, Italy.
    Chakaya, J. M.
    Kenyatta Univ, Dept Med Therapeut & Dermatol, Nairobi, Kenya.;Univ Liverpool Liverpool Sch Trop Med, Dept Clin Sci, Liverpool, Merseyside, England.
    Cirillo, D. M.
    IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Emerging Bacterial Pathogens Unit, Milan, Italy.
    Cho, J. G.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.;Parramatta Chest Clin, Parramatta, NSW, Australia.
    Ambrosio, L. D.
    Publ Hlth Consulting Grp, Lugano, Switzerland.
    Dalcolmo, M. P.
    Funda Oswaldo Cruz Fiocruz, Reference Ctr Helio Fraga, Rio De Janeiro, RJ, Brazil.
    Denti, P.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
    Dheda, K.
    Univ Cape Town, Ctr Lung Infect & Immun, Div Pulmonol, Dept Med, Cape Town, South Africa.;Univ Cape Town, UCT Lung Inst, Cape Town, South Africa.;Univ Cape Town Lung Inst, Cape Town, South Africa.;South African MRC Ctr Study Antimicrobial Resista, Cape Town, South Africa.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London, England.
    Fox, G. J.
    Univ Sydney, Fac Med & Hlth, Sydney Med Sch, Sydney, NSW, Australia.;Woolcock Inst Med Res, Glebe, NSW, Australia.
    Hesseling, A. C.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa.
    Kim, H. Y.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.
    Koser, C. U.
    Univ Cambridge, Dept Genet, Cambridge, England.
    Marais, B. J.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Childrens Hosp Westmead, Dept Infect Dis & Microbiol, Westmead, NSW, Australia.
    Margineanu, I
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.
    Martson, A. G.
    Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Torrico, M. Munoz
    Inst Nacl Enfermedades Resp, Clin TB, Ciudad De Mexico, Mexico.
    Nataprawira, H. M.
    Univ Padjadjaran, Hasan Sadikin Hosp, Fac Med, Dept Child Hlth,Div Paediat Respirol, Bandung, Indonesia.
    Ong, C. W. M.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Infect Dis Translat Res Programme, Singapore, Singapore.;Natl Univ Singapore, Inst Hlth Innovat & Technol iHealthtech, Singapore, Singapore.;Natl Univ Singapore Hosp, Dept Med, Div Infect Dis, Singapore, Singapore.
    Otto-Knapp, R.
    German Cent Comm TB DZK, Berlin, Germany.
    Peloquin, C. A.
    Univ Florida, Infect Dis Pharmacokinet Lab, Pharmacitherapy & Translat Res, Coll Pharm, Gainesville, FL USA.
    Silva, D. R.
    Univ Fed Rio Grande do Sul, Fac Med, Porto Alegre, RS, Brazil.
    Ruslami, R.
    Univ Padjadjaran, Fac Med, TB HIV Res Ctr, Bandung, Indonesia.;Univ Padjadjaran, Fac Med, Dept Biomed Sci, Div Pharmacol & Therapy, Bandung, Indonesia.
    Santoso, P.
    Univ Padjadjaran, Fac Med, Dept Internal Med, Div Respirol & Crit Care,Hasan Sadikin Gen Hosp, Bandung, Indonesia.
    Savic, R. M.
    Univ Calif San Francisco, Sch Pharm, Dept Bioengn & Therapeut Sci, Div Pulm & Crit Care Med, San Francisco, CA USA.;Univ Calif San Francisco, Sch Med, Div Pulm & Crit Care Med, Dept Bioengn & Therapeut Sci, San Francisco, CA USA.
    Singla, R.
    Natl Inst TB & Resp Dis, Dept TB & Resp Dis, New Delhi, India.
    Svensson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Nijmegen, Netherlands.
    Skrahina, A.
    Republican Res & Pract Ctr Pulmonol & TB, Minsk, BELARUS.
    van Soolingen, D.
    Natl Inst Publ Hlth & Environm, TB Reference Lab RIVM, Bilthoven, Netherlands.
    Srivastava, S.
    Univ Texas Hlth Sci Ctr Tyler, Dept Pulm Immunol, Tyler, TX USA.
    Tadolini, M.
    IRCCS Azienda Osped Univ Bologna, Infect Dis Unit, Bologna, Italy.;Alma Mater Studiorum Univ Bologna, Dept Med & Surg Sci, Bologna, Italy.
    Tiberi, S.
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London, England.
    Thomas, T. A.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA.
    Udwadia, Z. F.
    PD Hinduja Natl Hosp & Med Res Ctr, Mumbai, Maharashtra, India.
    Vu, D. H.
    Hanoi Univ Pharm, Natl Drug Informat & Adverse Drug React Monitorin, Hanoi, Vietnam.
    Zhang, W.
    Fudan Univ, Huashan Hosp, Shanghai Med Coll,Shanghai Key Lab Infect Dis & B, Natl Med Ctr Infect Dis,Dept Infect Dis, Shanghai, Peoples R China.
    Mpagama, S. G.
    Kilimanjaro Christian Med Univ Coll, Moshi, Tanzania.;Kibongoto Infect Dis Hosp, Siha, Kilimanjaro, Tanzania.
    Schon, T.
    Linköping Univ Hosp, Dept Infect Dis, Linköping, Sweden.;Linköping Univ, Inst Biomed & Clin Sci, Div Infect & Inflammat, Linköping, Sweden.;Linköping Univ, Kalmar Cty Hosp, Dept Infect Dis, Linköping, Sweden.
    Migliori, G. B.
    Grodno State Med Univ, Educ Inst, Grodno, BELARUS.
    Clinical standards for the dosing and management of TB drugs2022In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 26, no 6, p. 483-+Article in journal (Other academic)
    Abstract [en]

    Background: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice' for dosing and management of TB drugs.

    Methods: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.

    Results: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.

    Conclusion: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

  • 33.
    Alffenaar, Jan-Willem C.
    et al.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney Fac Med & Hlth, Sch Pharm, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia..
    de Steenwinkel, Jurriaan E. M.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    Diacon, Andreas H.
    TASK, Cape Town, South Africa..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Srivastava, Shashikant
    Univ Texas Hlth Sci Ctr Tyler, Dept Pulm Immunol, Tyler, TX USA..
    Wicha, Sebastian G.
    Univ Hamburg, Inst Pharm, Dept Clin Pharm, Hamburg, Germany..
    Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation of in vitro, in vivo methodologies and human studies2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 1063453Article, review/survey (Refereed)
    Abstract [en]

    There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field.

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  • 34. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 4, p. 470-476Article, review/survey (Refereed)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

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  • 35.
    Alhariri, Batul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Antipsykotiska läkemedel i relation till spel och impulskontrollstörningar i patienter med neurologiska sjukdomar2024Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Bakgrund: Det har visat sig under de senaste 20 åren att användning av aripiprazol ökar risken för spel- och impulskontrollstörningar. Aripiprazol är ett första generationens antipsykotiska läkemedel och fungerar som en partiell serotonin 5-HT1A-receptoragonist, en 5-HT2A-receptorantagonist och en specifik partiell dopamin D2/D3-agonist. 

    Syfte: Syftet är att studera hur förekomsten av spel- och impulskontrollstörningar skiljer sig mellan neurologiska patienter som får Aripiprazol respektive andra antipsykotiska läkemedel som komplement till behandling med Parkinsons sjukdom eller Restless Legs Syndrome. 

    Metoder: Detta är en retrospektiv registerstudie som analyserar läkemedelsdata som täcker åren 2005 till 2022 och patientdata som innehåller diagnoser för Parkinsons sjukdom och Restless Legs Syndrome samt spel- och impulskontrollstörningar. Data analyserades genom att mäta frekvensen av recept för att analysera antalet händelser av spelstörningar, impulskontrollstörningar och kontrollgrupper hos personer med Parkinsons sjukdom och Restless Legs Syndrome. 

    Resultat: Det finns en tydlig skillnad mellan de antipsykotiska läkemedlen. Första och andra generationens antipsykotika, inklusive litium, olanzapin, levomepromazin och aripiprazol, har visats vara associerade med störningar i spel och impulskontroll hos patienter med Parkinsons sjukdom och Restless Legs Syndrome. Aripiprazol visade sig ha det starkaste sambandet med störningar i impulskontroll och litium hade det starkaste sambandet med spelstörningar hos personer med Restless Legs Syndrome. Dessutom hade Levomepromazin det starkaste sambandet med störningar i impulskontroll och Olanzapin hade det starkaste sambandet med spelstörningar hos personer med Parkinsons sjukdom. 

    Slutsatser: Denna studie har konsekvenser för framtiden då den hjälper till att veta om det finns risk för spel- och impulskontrollstörningar vid användning av antipsykotiska läkemedel. Så det hjälper till att skapa maximal säkerhet för antipsykotiska läkemedel och hantera risken för spel- och impulskontrollstörningar på bästa möjliga sätt.

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  • 36.
    Ali, Ehood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Harvard Medical school / Boston Children's Hospital.
    The Role of the Glycine Receptor’s Alpha 2Subunit in the Behavior of Mice2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 37.
    Alimohammadi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Neurophysiological Measures of Efficacy and Safety for Botulinum Toxin Injection in Facial and Bulbar Muscles: Special Considerations2017In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 9, no 11, article id 352Article, review/survey (Refereed)
    Abstract [en]

    Botulinum toxin (BoNT) injections into facial and bulbar muscles are widely and increasingly used as medical treatments for cervical and facial dystonia, facial hemispasm, correction of facial palsy, hyperhidrosis, as well as cosmetic treatment of glabellar lines associated with grief and anger. Although BoNT treatment is generally considered safe, the diffusion of the toxin to surrounding muscles may result in complications, including difficulties swallowing, in a dose-dependent manner. The sensitivity of clinical examination for detecting adverse events after BoNT treatment is limited. Few reports have highlighted the potential effects on other muscles in the facial area due to the spreading of the toxin. The possibilities of spreading and thus unknown pharmacological BoNT effects in non-targeted muscles emphasise the importance of correct administration of BoNT in terms of dose selection, injection points, and appropriate effect surveillance. In this review article, we will focus on novel objective measures of efficacy and safety regarding BoNT treatment of facial muscles and the reasons why this is important.

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  • 38.
    Al-jasar, Marwa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Beta-sekretashämmare vid Alzheimers sjukdom2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Abstrakt

    Bakgrund: Alzheimers sjukdom (AD) är en av de vanligaste neurodegenerativa sjukdomarna och anses vara den främsta orsaken till nedsatt eller försämring av minnet hos äldre. De vanligaste symptomen på AD är förlust av intellektuell förmåga som så småningom resulterar i dysfunktion i det dagliga livet. Forskningar har visat att amyloida β-peptider kan ha en avgörande roll i den patologiska processen för neurodegenerativ sjukdom inklusive AD. Amyloid β-peptider är en nyckelmolekyl vid AD där en ansamling av detta peptid ansågs initiera den patologiska kaskaden av AD, inklusive bildandet av senila plack och neurofibrillära trassel vilket leder till neuronal förlust och demens. Med tanke på att AD patienter uppvisar ökad nivå av Aβ40-42 i både blodet och cerebrospinalvätskan, anses detta vara en biomarkör för sjukdomen. Därav används dessa biomarkörer för prognos och behandling av Alzheimer sjukdom. β-sekretashämmare blockerar den första hastighetsbegränsande proteolytiska klyvningen av amyloida prekursorpeptider. Detta bör resultera i produktionsreducering av aggregerande Aβ-peptider. Forskning pågår kring användandet av β-sekretashämmare för behandling av AD och dess kliniska relevans.

    Syfte: Syftet med detta fördjupningsprojekt är att undersöka om β-sekretashämmare påverkar Aβ-koncentrationen i cerebrospinalvätska och plasma. Samt att diskutera ifall reduceringen medför en inbromsning av de degenerativa processer som AD orsakar.

    Metod: Metoden som användes är en systematisk litteraturöversikt där fem studier granskades.

    Resultat: Baserat på de vetenskapliga originalartiklarna som använts har β-sekretashämmare minskat koncentrationen på β-amyloid i både cerebrospinalvätska och plasma med mer än 50 % hos alla män och kvinnor mellan 18–75 år.

    Slutsats: β-sekretashämmare reducerar Aβ-nivåerna. Flera kliniska studier behövs för att bekräfta effekten av denna minskning för att se om den har en klinisk betydelse.

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  • 39.
    Aljundi, Hanan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effekt av vitamin E ensam och i kombination med andra antioxidanter vid Alzheimers sjukdom.2022Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Alzheimers sjukdom är en neurodegenerativ sjukdom som inte kan botas och som förvärras gradvis med tiden. Sjukdomen kännetecknas av försämrat minne och över lag försämrade kognitiva förmågor. Neuropatologin bakom sjukdomen är uppkomsten av fibriller (neurofibrillarytangles) och plack (senile plaques), och dessutom försämrad synaptisk funktion och cellförlust. Det finns en skada som uppstår i hjärnan och som är associerad till åldrandet. Den är också utbredd i hjärnan vid Alzheimers sjukdom. Denna skada kallas för oxidativ skada, eller oxidativ stress, och förstör hjärnvävnader. Oxidativ stress är en nyckelmekanism som är associerad till sjukdomsdebut och progression, och den kan modifieras genom kost och/eller antioxidanttillskot. Alfa-tokoferol (huvudformen av vitamin E) är en viktig lipofil antioxidant hos människor och är nödvändig för hjärnans normala funktion.Syfte: Syftet med detta litteraturarbete är att undersöka effekten av vitamin E ansam och tillsammans med andra antioxidanter och ta reda på om de kan påverka sjukdomens biomarkörer hos äldre som har diagnosen till Alzheimers.Metod: Detta är ett litteraturarbete som är baserad på vetenskapliga artiklar. Sökningen gjordes huvudsakligen i databasen PubMed. Sex artiklar inkluderades för att besvara syftet i resultat delen. Relevanta artiklar som besvarar syftet, ficks efter avgränsningen enligt inklusionskriterier. Artiklarna är originalartiklar, skrivna på engelska, handlar om att patienterna ska vara diagnostiserades med Alzheimers sjukdom, dessutom att artiklarna ska handla också om effekten av vitamin E ensam och i kombination med andra antioxidanter som används vid behandlingen av Alzheimers sjukdom. Artiklar som inte uppfyllde inklusionskriterier som passar syftet, exkluderades.Resultat: Signifikant minskningar på oxidativ stress och HCy observerades endast när det visades en ökning av glutation (i erytrocyter) och en minskning av sickle-erytrocyter hos patienter som behandlades med formel F. Tillskottet med vitamin E och C signifikant ökade koncentrationerna av både vitaminer i plasma och CSF. Administrering av vitamin E i 400 mg/dag i 6 månader till Alzheimers patinter, delvis vände Alzheimers associerade förändringar i oxidativ stress markörer.Slutsats: Vitamin E, som är den viktigaste lipofila antioxidanten, verkade vara effektiv behandling i monoterapi och i kombination med andra antioxidanter genom att påverka biomarkörer och vissa symtomav Alzheimers sjukdom. Detta väcker intresse för att forska vidare i ämnet och bedöma om den kan varaen pålitlig behandling som ska användas i varje behandling av Alzheimers sjukdom.

  • 40.
    Alm, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Proteomic Characterization of Induced Developmental Neurotoxicity2009Doctoral thesis, comprehensive summary (Other academic)
    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.

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  • 41.
    Al-Mahdi Al-Karagholi, Mohammad
    et al.
    Univ Copenhagen, Danish Headache Ctr, Dept Neurol, Glostrup, Denmark.
    Møller Hansen, Jakob
    Univ Copenhagen, Danish Headache Ctr, Dept Neurol, Glostrup, Denmark; Rigshosp Glostrup, Danish Knowledge Ctr Headache Disorders, Glostrup, Denmark.
    Abou-Kassem, Dalia
    Univ Copenhagen, Danish Headache Ctr, Dept Neurol, Glostrup, Denmark.
    Koldbro Hansted, Anna
    Univ Copenhagen, Rigshosp Glostrup, Fac Hlth & Med Sci, Glostrup Res Inst,Danish Headache Ctr, Glostrup, Denmark.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Vécsei, László
    Univ Szeged, Dept Neurol, Szeged, Hungary; Univ Szeged, MTA SZTE Neurosci Res Grp, Szeged, Hungary.
    Jansen-Olesen, Inger
    Univ Copenhagen, Rigshosp Glostrup, Fac Hlth & Med Sci, Glostrup Res Inst, Danish Headache Ctr, Glostrup, Denmark.
    Ashina, Messoud
    Univ Copenhagen, Danish Headache Ctr, Dept Neurol, Glostrup, Denmark; Rigshosp Glostrup, Danish Knowledge Ctr Headache Disorders, Glostrup, Denmark.
    Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers2021In: Pharmacology Research & Perspectives, E-ISSN 2052-1707, Vol. 9, no 2, article id e00741Article in journal (Refereed)
    Abstract [en]

    The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.

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  • 42.
    Almqvist, Helena
    et al.
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Axelsson, Hanna
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Jafari, Rozbeh
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Dan, Chen
    School of Biological Sciences, Nanyang Technological University.
    Mateus, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Haraldsson, Martin
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Larsson, Andreas
    School of Biological Sciences, Nanyang Technological University.
    Martinez-Molina, Daniel
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Nordlund, Pär
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil2016In: Nature Communications, E-ISSN 2041-1723, Vol. 7, article id 11040Article in journal (Refereed)
    Abstract [en]

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.

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  • 43.
    Alnuaimy, Ranin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Granskning av läkemedelsinformation i FASS gällande risk under graviditet och amning2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: År 1978 introduceras ett klassificeringssystem i FASS (Farmaceutiska specialiteter i Sverige) för att underlätta bedömningen vid förskrivning av läkemedel till gravida och ammande kvinnor. Detta gäller bedömningen av ett läkemedels risk för bieffekter under graviditet och amning utifrån vilken kategori det placeras i. När Sverige 1995 går med i EU beslutar den medicinska expertgruppen att inte längre granska FASS- texter utan lämna över uppgiften till själva läkemedelsföretagen. Syfte: I detta projektarbete jämförs FASS-texter under rubrikerna Graviditet och Amning med läkemedelskategorin som de är placerade i. Metod och Material: Läkemedelsprodukter som granskas i arbetet är totalt 422 produkter med indikationsområden för andningsorgan (ATC- grupp R) samt ögon och öron (ATC-grupp S). Läkemedelsgrupperna är intressanta eftersom de innehåller läkemedel som rekommenderas under graviditet samt amning som till exempel inhalationspreparat mot astma eller ögondroppar mot glaukom. De texter som granskas har hämtats från FASS hemsida www.fass.se. Ytterligare information såsom namn, form, styrka, beredningsform och tillverkare för läkemedlen har hämtats från NPL (Nationellt Produktregister för Läkemedel). Resultat: Studien visar att ca 5 % respektive 13 % av läkemedel inom indikationsområden Andningsorgan (ATC-grupp R) samt Ögon och Öron (ATC-grupp S) är felklassificerade i förhållande till kriterierna för en FASS-text. Procenten inkluderar även läkemedel med saknad klassificering. Diskussion: Eftersom granskning av FASS-texter inte sköts av någon myndighet längre är läkemedelsföretagen själva ansvariga för informationen som står i FASS idag. Detta har lett till problem i form av saknad klassificering eller fel klassificering av läkemedel i FASS-texter något som är viktigt ur graviditets- och amningsperspektiv. Problemet bör uppmärksammas av ansvariga läkemedelsföretag och kontrollmyndigheter.

  • 44.
    Al-Obaidi, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Endocannabinoider som mål för nya läkemedel vid Alzheimer sjukdom2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Alzheimers sjukdom (AD) är en neurodegenerativ sjukdom, där hjärnatrofi och minnesförlust ses på grund av en irreversibel celldöd. Sjukdomen drabbar framför allt människor i åldern 65 år eller äldre. Mikroskopiskt ses ansamlingar av β-amyloida plack och neurofibriller. Vid sjukdomen ses en långvarig inflammatorisk process i hjärnan som troligen uppkommer på grund av ökade halter av reaktiva syreradikaler (ROS) intracellulärt. Forskare har observerat att mängden ROS ökar i de neuron som omges av β-amyloida plack (ökad ansamling av β-amyloid leder till neurodegeneration). Tidigare studier har visat att det endocannabinoida systemet spelar en viktig roll vid inflammatoriska nervsjukdomar. Mekanismerna för hur endocannabinoider påverkar hjärnans aktivitet är långt ifrån kända. Endocannabioider som anandamid och arachidonoylglycerol (2-AG) kan modulera cellulära processer och därmed utöva både anti-inflammatoriska och anti-excitotoxiska effekter. Syftet med detta arbete var att undersöka den neuroprotektiva benägenhet hos 2-AG. För att kunna utföra arbetet användes humana neuroblastoma SH-SY5Y celler, som behandlades med det toxiska ämnet t-butylväteperoxid (t-BHP). t-BHP inducerar oxidativ stress i cellerna. Cellerna behandlades sedan med t-BHP i närvaro av endocannabinoiden 2-AG. Cellöverlevaden bestämdes med MTT-metoden. Resultaten uppvisade en dos-beroende celldöd med tBHP. 2-AG kunde motverka t-BHP inducerad toxicitet och ökade signifikant cellöverlevnaden. Utifrån resultaten observerades att cellöverlevnad hade signifikant ökat i närvaro 2-AG. Resultaten från denna studie visar på att 2-AG uppvisar en neuroprotektiv egenskap. Vidare studier behövs för att utreda mekanismerna bakom dess neuroprotektiva egenskaper.

  • 45.
    Al-Shammari, Rotana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nya behandlingsmål för att minska levodopainducerade dyskinesier vid Parkinsons sjukdom2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: Parkinsons sjukdom (PD) är en åldersrelaterad sjukdom och bland de vanligaste neurodegenerativa sjukdomarna. Till neurodegenerativa sjukdomar hör de sjukdomarna som leder till förtvining av centrala nervsystemet i hjärnan i form av förlust av nervceller eller aggregering av proteiner. Vid PD är det förlust av dopaminerga nervceller som förefaller i ett visst område i hjärnan, så kallad substantia nigra (SN). PD kännetecknas av motoriska symtom i form av stelhet, skakningar och rörelsehämning. PD behandlas idag i första hand med levodopa. Levodopa omvandlas till dopamin i hjärnan vilket ger den önskade effekten av att höja dopaminhalten i hjärnan. Nackdelen med levodopa är utveckling av ofrivillig överrörlighet, s.k. levodopainducerade dyskinesier (LID), efter ca 7-10 år av behandlingen. Studier har visat att rökare har mindre risk för PD vilket väckte intresse för att forska på nikotinets roll. Andra studier har bevisat ökad aktivitet av glutamat vid PD vilket ledde till att vidare undersöka vad hämning av glutamatreceptorer kan ge för effekt.

    Syfte: Syftet med detta arbete var att undersöka nya behandlingsstrategier för att minska risken för LID.

    Metod: Arbete är en litteraturstudie baserad på sekundärdata från vetenskapliga artiklar och relevant litteratur. Litteratursökningen gjordes på olika databaser, framförallt PubMed.

    Resultat: Administrering av vissa typer av nikotinreceptor agonister innan intag av levodopa kan minska LID med ca 50%. En hämning av LID har även setts vid intag av olika antagonister till glutamatreceptorer.

    Slutsats: Flera substanser som verkar på olika nikotin- och glutamatreceptorer visar en bra effekt mot LID. En kombination av dessa substanser kan leda den framtida forskningen till den efterlängtade optimala behandlingen i att förebygga LID samtidigt som den ökar dopaminhalten i SN. 

  • 46.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    From Food Preference to Craving: Behavioural Traits and Molecular Mechanisms2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preference for palatable and energy-dense foods may be a risk factor for body weight gain and has both genetic and environmental components. Once obesity develops in an individual, weight loss is difficult to achieve. Indeed, obesity is often characterized by repeated attempts to reduce the overconsumption of energy-dense foods, followed by food craving and relapse to overconsumption. Relapse and loss of control over intake are observed also in drug addicts, and it has been shown that obesity and drug addiction not only share behavioural features but also neural circuitry, e.g. the mesolimbic dopamine pathway. In this thesis, we sought to investigate the mechanisms related to food preferences and craving using animal models previously used in addiction research.

    The risk of gaining weight may implicate behavioural traits and emotional states. We showed in rats that a risk-taking behavioural profile was associated both with increased preference for a high-fat (HF) diet and with increased motivational response to a palatable high-sucrose (HS) diet. Hypothalamic urocortin 2 expression was associated with the preference for the HF diet. We also tested the hypothesis that consumption of HS and HF diets separately or provided simultaneously (HFHS) affect anxiety-like behaviour and locomotion.

    Furthermore, we showed that withdrawal from HFHS food affects diet-induced obesity-prone (OP) and obesity-resistant (OR) animals differently. OP animals had increased motivation (craving) for HS food pellets as measured by the operant self-administration technique during withdrawal. Dopamine receptor expression in the striatum differed between OP and OR animals both at access to HFHS and during withdrawal. This strongly implicates dopaminergic signaling in the OP phenotype.

    In humans, food preferences may be monitored using questionnaires. We analyzed food preference data from parents of preschool children, and identified an inverse association of parental preference for high-fat high-protein food and overweight in children.

    In conclusion, we have employed animal models previously used in the addiction field to identify molecular mechanisms related both to food preference and vulnerability to obesity, and to food craving associated with withdrawal from palatable food. These findings add to our current understanding of obesity.

     

    List of papers
    1. Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
    Open this publication in new window or tab >>Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
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    2009 (English)In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, p. 193-202Article in journal (Refereed) Published
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

    Keywords
    Anxiety, corticotropin-releasing factor receptor, dietary fat, elevated plus maze, exploratory behavior, food preferences, multivariate concentric square field, novelty seeking, palatable, urocortin 2, Wistar
    National Category
    Pharmacology and Toxicology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-117598 (URN)10.1111/j.1601-183X.2008.00464.x (DOI)000263756100007 ()19077174 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2022-01-28Bibliographically approved
    2. Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
    Open this publication in new window or tab >>Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Obesity may be induced in rodents by long-term access to dietary fat. Such treatment has been reported to have behavioural effects including reduced anxiety-like behaviour and diminished operant responding for psychostimulants. It is unclear whether such effects are secondary to metabolic changes due to excess body weight, or to the extended access to palatable food reward. The aim of this study was to investigate the effects of a short palatable diet exposure (10 days) on performance in the open field test of novelty-induced locomotion and anxiety-like behaviour in rats. We subjected rats to a free-choice high-fat or high-sugar diet, or both, for a period of 10 days. Increased caloric intake was observed in all groups but body weight at Day 10 did not differ from chow-fed controls. We report that consumption of the free-choice high-fat diets was associated with higher novelty-induced activity and reduced anxiety-like behaviour in the open field test. In addition, we used RT-PCR to show that the high-fat group had 39% higher expression of mu opioid receptor in the lateral hypothalamus, and that tyrosine hydroxylase expression was elevated more than two-fold in the ventral tegmental area of rats with access to both high-fat and high-sugar. In conclusion, these results show that subchronic exposure to a free-choice high-fat diet induces behavioural adaptations such as elevated locomotor activity and attenuated experimental anxiety. The changes observed in gene expression related to reward after high-fat diet exposure indicate that these behavioural adaptations are related to reward function.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-119489 (URN)
    Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2013-01-08
    3. Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
    Open this publication in new window or tab >>Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
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    2009 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 454, no 3, p. 193-197Article in journal (Refereed) Published
    Abstract [en]

    Anxiety has been implicated in obesity and in the overconsumption of highly palatable foods such as those high in fat, sugar, or both. Also, the novelty-seeking trait has been associated with failure in weight-loss programs. The aim of this study was to investigate the associations of experimental anxiety and the self-administration of sucrose and high fat pellets in non-food deprived rats across different operant schedules. Male Wistar rats were subjected to the elevated plus-maze test (EPM) of anxiety-like behavior. The rats were tested for fixed ratio 5 (FR5) and progressive ratio (PR) operant responding for 50% sucrose, 95% sucrose, and high-fat pellets. PR active lever press response for 95% sucrose, but not the other pellet types, was correlated to % time spent on open arms (P=0.019) in the EPM. On the FR5 schedule, activity (closed arm entries) was correlated to the self-administration of 50% sucrose (P=0.027) and high-fat (P=0.002). This indicates an association of novelty-induced activity and self-administration of palatable food in sated rats, as well as a specific association of PR lever press response for 95% sucrose and low anxiety-like behavior. It has been argued that such active lever press response on PR may be interpreted as craving for the reinforcer; thus, our findings indicate an inverse relationship of experimental anxiety and craving for sucrose. This connection may have implications for human situations, since anxiety and novelty-seeking have been associated with obesity and failure in weight-loss programs.

    Place, publisher, year, edition, pages
    Elsevier, 2009
    Keywords
    Craving; Sucrose, Dietary fat, Progressive ratio, Anxiety, Novelty-seeking
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-117599 (URN)10.1016/j.neulet.2009.03.045 (DOI)000265275500005 ()19429082 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2022-01-28Bibliographically approved
    4. Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    Open this publication in new window or tab >>Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    2009 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 204, no 3, p. 431-443Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION:

    Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.

    MATERIALS AND METHODS:

    In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.

    RESULTS AND DISCUSSION:

    After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.

    CONCLUSION:

    The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.

    Keywords
    Diet-induced obesity, Operant self-administration, Progressive ratio, Fixed ratio, Whole-animal physiology
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-117600 (URN)10.1007/s00213-009-1474-y (DOI)000266085700006 ()19205668 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2022-01-28Bibliographically approved
    5. Downregulation of nucleus accumbens D1 and D2 receptor expression occurs upon exposure to and persists long-term after withdrawal from palatable food: conclusions from diet-induced obesity models
    Open this publication in new window or tab >>Downregulation of nucleus accumbens D1 and D2 receptor expression occurs upon exposure to and persists long-term after withdrawal from palatable food: conclusions from diet-induced obesity models
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    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-119449 (URN)
    Note
    The nucleus accumbens (NAcc) mediates feeding reward; its activity reflects tastants’ hedonic value. The NAcc dopamine guides immediate responses to reward, however, its involvement in establishing long-term responses after a period of exposure to palatable foods has not been defined. Furthermore, reward-driven overeating propels weight increase, but the scale of weight gain depends on animals’ obesity-prone (OP) or -resistant (OR) phenotype. It is unclear whether responses of NAcc dopamine to palatable foods depend on susceptibility to obesity. We investigated the effect of restricted and unrestricted extended access to high-fat high-sugar (HFHS) diet on expression of genes encoding dopamine receptors in the NAcc of OP and OR rats. We examined persistence of HFHS diet-induced changes in D1 and D2 gene expression in OP and OR rats subjected to HFHS withdrawal by receiving bland chow for 18 days after HFHS. Effects of restricted access to HFHS by pair-feeding to bland chow-fed controls were also studied. Using RT-PCR, we found that NAcc D1 mRNA was downregulated after long-term HFHS access in OP vs. OR animals. The effect persisted after 18 days of HFHS withdrawal. Noteworthy, even restricted HFHS led to downregulation of D1 as well as of D2 mRNA levels compared to chow-fed controls. Detection of concurrent expression changes of mu and kappa opioid receptors in the NAcc and caudate putamen confirmed their link to the effects of feeding reward withdrawal. We conclude that exposure to palatability has lasting consequences for the NAcc dopamine system, perhaps underlying the persistent search for feeding reward. The fact that the NAcc D1 expression changes long-term in OP animals after both un- and restricted exposure to palatability and extends well into the reward discontinuation phase, implicates the D1 receptor with the propensity to overeat and, in effect, gain weight in obesity prone individuals.Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2010-03-01
    6. Parental food preferences are associated with body weight disturbance in preschool children
    Open this publication in new window or tab >>Parental food preferences are associated with body weight disturbance in preschool children
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Parental factors such as stress induced by parenting and certain food preferences are suspected to promote obesity in preschool children. In this context, especially the intake of dietary fat is assumed to play a key role for the children’s risk to become obese. Here we analyzed eating behaviors in parents of 3-year-olds in order to identify parental traits that are associated with body weight in these children. We also tested for possible interactions between psychosocial factors such as stress induced by parenting and parental food cravings. Questionnaires were sent out to 1300 parents whose children’s body weight was measured during ambulatory medical care visits (parental response rate 70.4%). Using the Food Craving Inventory scale allowed examining parental preferences for the following food categories:  high-fat/high-protein, sweets, carbohydrates, and fast food. Psychosocial stress caused by parenting was assessed with the Swedish Parenthood Stress Questionnaire (SPSQ). Our main finding was that the parental preference for foods rich in high-fat/high-protein nutrients displayed an inverse U-shaped function to the children’s body weight such that low preference for this category was associated with both overweight and underweight in offspring. Parental preference for sweet-foods were associated with higher odds for developing overweight in early childhood. The level of parental food preferences was significantly modulated by stress induced by parenting. In conclusion, we show that parental food preference is affected by stress and is associated with the body weight status of their children. The results suggest that parental intake of high-fat/high-protein foods protects against weight disturbances in preschool children.

    Identifiers
    urn:nbn:se:uu:diva-119472 (URN)
    Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2010-03-01
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  • 47.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Gastambide, F.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Wang, R. A. H.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Dam, S. A.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Tricklebank, M.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 21-22, p. 4017-4031Article in journal (Refereed)
    Abstract [en]

    Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms. In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 mu g/side) on performance in this task. In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4). Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.

  • 48.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jonsson, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Minnesota Obesity Center, VA Medical Center, Minneapolis, MN, USA.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 22009In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, p. 193-202Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

  • 49.
    Alskär, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mechanism-Based Modelling of Clinical and Preclinical Studies of Glucose Homeostasis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glucose is an important nutrient and energy source in the body. However, too high concentration in the blood is harmful and may lead to several complications developing over time. It was estimated that 5 million people in the world died from complications related to diabetes during 2015. Several hormones and physiological factors are involved in the regulation of glucose homeostasis. To evaluate different aspects of glucose homeostasis and the effect of interventions, such as pharmacological treatment, glucose tolerance tests can be performed. In a glucose tolerance test glucose is administered either orally or intravenously, blood is sampled frequently and analyzed for different biomarkers. Mechanism-based pharmacometric models is a valuable tool in drug development, which can be applied to increase the knowledge about complex systems such as glucose homeostasis, quantify the effects of drugs, generate more information from clinical trials and contribute to more efficient study design. In this thesis, a new comprehensive mechanism-based pharmacometric model was developed. The model is capable of describing the most important aspects of glucose homeostasis during glucose tolerance test in healthy individuals and patients with type 2 diabetes, over a wide range of oral and intravenous glucose doses. Moreover, it can simultaneously describe regulation of gastric emptying and glucose absorption, regulation of the incretin hormones GLP-1 and GIP, hepatic extraction of insulin and the incretin effect, regulation of glucagon synthesis and regulation of endogenous glucose production. In addition, an interspecies scaling approach was developed by scaling a previously developed clinical glucose insulin model to describe intravenous glucose tolerance tests performed in mice, rats, dogs, pigs and monkeys. In conclusion, the developed mechanism-based models in this thesis increases the knowledge about short term regulation of glucose homeostasis and can be used to investigate combination treatments, drugs with multiple effects, and translation of drug effects between species, leading to improved drug development of new antidiabetic compounds.

    List of papers
    1. Model-Based Interspecies Scaling of Glucose Homeostasis
    Open this publication in new window or tab >>Model-Based Interspecies Scaling of Glucose Homeostasis
    2017 (English)In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 6, no 11, p. 778-786Article in journal (Refereed) Published
    Abstract [en]

    Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0.75 and 1, for clearances and volumes, respectively, could describe the data well with some species-specific adaptations: dogs and pigs showed slower first phase insulin secretion than expected from the scaling, pigs also showed more rapid insulin dependent glucose elimination, and rodents showed differences in glucose effectiveness. The resulting scaled IGI model was shown to accurately predict external preclinical IVGTT data and may be useful in facilitating translations of preclinical research into the clinic.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2017
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-339699 (URN)10.1002/psp4.12247 (DOI)000418823400009 ()28960826 (PubMedID)
    Available from: 2018-01-29 Created: 2018-01-29 Last updated: 2020-12-17Bibliographically approved
    2. Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
    Open this publication in new window or tab >>Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
    Show others...
    2016 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 56, no 3, p. 340-348Article in journal (Refereed) Published
    Abstract [en]

    The integrated glucose-insulin (IGI) model is a previously published semi-mechanistic model, which describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semi-physiological model developed performed better than previously published empirical models and allows for better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.

    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-259411 (URN)10.1002/jcph.602 (DOI)000370162700011 ()26224050 (PubMedID)
    Available from: 2015-08-03 Created: 2015-08-03 Last updated: 2018-02-26
    3. Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
    Open this publication in new window or tab >>Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
    Show others...
    2017 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 121, no 4, p. 290-297Article in journal (Refereed) Published
    Abstract [en]

    The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP-1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.

    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-279065 (URN)10.1111/bcpt.12792 (DOI)000409507900013 ()28374974 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, 115156
    Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-02-26Bibliographically approved
    4. Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
    Open this publication in new window or tab >>Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Pharmacology and Toxicology
    Research subject
    Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-343114 (URN)
    Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26
    5. An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
    Open this publication in new window or tab >>An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Pharmacology and Toxicology
    Research subject
    Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-343115 (URN)
    Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26
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  • 50.
    Alskär, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bagger, Jonatan I
    Eriksson, Sara
    Holst, Jens J
    Knop, Filip K
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vilsbøll, Tina
    Kjellsson, Maria C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 DiabetesManuscript (preprint) (Other academic)
1234567 1 - 50 of 1217
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