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  • 1.
    Aakjær, Mia
    et al.
    Department of Drug Design and Pharmacology, Pharmacovigilance Research Center, University of Copenhagen, Copenhagen, Denmark.
    De Bruin, Marie Louise
    Department of Pharmacy, Copenhagen Centre for Regulatory Science (CORS), University of Copenhagen, Copenhagen, Denmark; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
    Kulahci, Murat
    Luleå University of Technology, Department of Social Sciences, Technology and Arts, Business Administration and Industrial Engineering. Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, Denmark.
    Andersen, Morten
    Department of Drug Design and Pharmacology, Pharmacovigilance Research Center, University of Copenhagen, Copenhagen, Denmark.
    Surveillance of Antidepressant Safety (SADS): Active Signal Detection of Serious Medical Events Following SSRI and SNRI Initiation Using Big Healthcare Data2021In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 44, p. 1215-1230Article in journal (Refereed)
    Abstract [en]

    Introduction The current process for generating evidence in pharmacovigilance has several limitations, which often lead to delays in the evaluation of drug-associated risks.

    Objectives In this study, we proposed and tested a near real-time epidemiological surveillance system using sequential, cumulative analyses focusing on the detection and preliminary risk quantification of potential safety signals following initiation of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

    Methods We emulated an active surveillance system in an historical setting by conducting repeated annual cohort studies using nationwide Danish healthcare data (1996–2016). Outcomes were selected from the European Medicines Agency's Designated Medical Event list, summaries of product characteristics, and the literature. We followed patients for a maximum of 6 months from treatment initiation to the event of interest or censoring. We performed Cox regression analyses adjusted for standard sets of covariates. Potential safety signals were visualized using heat maps and cumulative hazard ratio (HR) plots over time.

    Results In the total study population, 969,667 new users were included and followed for 461,506 person-years. We detected potential safety signals with incidence rates as low as 0.9 per 10,000 person-years. Having eight different exposure drugs and 51 medical events, we identified 31 unique combinations of potential safety signals with a positive association to the event of interest in the exposed group. We proposed that these signals were designated for further evaluation once they appeared in a prospective setting. In total, 21 (67.7%) of these were not present in the current summaries of product characteristics.

    Conclusion The study demonstrated the feasibility of performing epidemiological surveillance using sequential, cumulative analyses. Larger populations are needed to evaluate rare events and infrequently used antidepressants.

  • 2. Abbasi, Arshad Mehmood
    et al.
    Khan, Mir Ajab
    Khan, Nadeem
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Shah, Munir H
    Ethnobotanical survey of medicinally important wild edible fruits species used by tribal communities of Lesser Himalayas-Pakistan2013In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 148, no 2, p. 528-536Article in journal (Refereed)
    Abstract [en]

    Ethnopharmacological relevance: Present survey was conducted to explore ethnomedicinal uses and cultural importance of wild edible fruits species by the inhabitants of Lesser Himalayas-Pakistan. Materials and methods: Information was obtained through informed consent semi-structured interviews, questionnaires, market survey, focus group conversation, unceremonious dialogue and village walks with key informants. Cultural significance of each species was calculated based on use report by participants at each study site. Results: A total of 35 wild edible fruits belonging to 21 genera and 17 families were used for the treatment of various ailments and consumed. Rosaceae was found dominating family with (8 spp.), followed by Moraceae (6 spp.), Rhamnaceae (5 spp.), Palmae and Vitaceae (2 spp. each) and remaining families were represented by one species each. Fruits (48%) were found highly utilized plant parts, followed by leaves (34%), bark, flowers and seeds (4% each), branches, latex and roots (2% each). Water was used as a medium for preparation while milk, ghee, oil, egg and butter are used for application. Modes of preparation were fall into seven categories like fresh parts eaten raw (38%), powder (24%), decoction (20%), extract (12 %), paste (4%), juice and latex (2% each). Based on cultural important index (CI) Morus nigra was found most significant species within top ten fruit plants followed by Morus alba, Olea ferruginea, Berberis lycium, Pyrus pashia, Ficus carica, Ficus palmata, Ziziphus mauritiana, Diospyros lotus and Ziziphus nummularia. Conclusions: Traditional uses of wild edible plant depend mainly on socio-economic factors rather than climatic conditions or wealth of flora. Use reports and citation demonstrated that there is a common cultural heritage regarding the gathered food plants. Further investigation is required for Antioxidant study, essential and toxic components, pharmacological applications; dietary requirements and biotechnological techniques to improve yields.

    (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  • 3.
    Abbasi Aval, Negar
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Khati, Vamakshi
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Pettersson, Torbjörn
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Russom, Aman
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Layer-by-Layer cellulose nanofibril coating for spheroid formation combined with decellularized extracellular matrix for 3D tumor modelingManuscript (preprint) (Other academic)
  • 4.
    Abbasi Aval, Negar
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Khati, Vamakshi
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Russom, Aman
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.
    Pettersson, Torbjörn
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology.
    Influence of Decellularized Extra Cellular Matrix on 3D spheroids formed on Layer-by-Layer cellulose nanofibril/Polyelectrolytes coating as an in-vitro model for Hepatocellular CarcinomaManuscript (preprint) (Other academic)
  • 5.
    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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  • 6.
    Abdal Hadi, Jehan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hur skiljer sig traditionella från nyare generationer antipsykotika åt vad gäller biverkningen viktökning?2008Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpStudent thesis
    Abstract [sv]

    Antipsykotiska läkemedel är basen för behandling av schizofreni, en psykisk sjukdom som uppträder redan hos unga människor. Symtomen vid schizofreni brukar delas in i positiva symtom (hallucinationer, vanföreställningar, paranoida tankar), negativa symtom (koncentrationssvårigheter, nedsatt språk- och tankeförmåga, minskat intresse för omgivningen, och initiativlöshet), samt kognitiva symtom (minnesproblem, problem med uppmärksamhet och koncentration).

    Antipsykotiska läkemedel delas in i typiska (den äldre generationen) och atypiska (den nyare generationen) antipsykotika. För båda grupperna antipsykotiska läkemedel finns det risk för biverkningar. De vanligaste biverkningarna vid behandling med den äldre generationen antipsykotika är extrapyramidala biverkningar. En biverkning som förefaller mer specifik för de nya atypiska preparaten är viktökning, vilken även kan orsaka utveckling av många allvarliga sjukdomstillstånd.

    Syftet med detta arbete var att jämföra typiska och atypiska antipsykotiska läkemedel med avseende på utveckling av viktökning.

    För att få svar på min frågeställning har en litteraturstudie av fem vetenskapliga artiklar genomförts. De vetenskapliga artiklarna har hittats genom databassökningar i PubMed, medan övriga fakta har hämtats från andra källor.

    Resultatet av de vetenskapliga artiklarna visar att det finns skillnader mellan traditionella och nyare generationer antipsykotika vad gäller tendens att orsaka viktökning. Med några undantag, är flera antipsykotiska läkemedel, som tillhör den nyare generationen, associerade med högre risk för utveckling av viktökning jämfört med den äldre generationen antipsykotika. Viktökning orsakas mest av klozapin, följt av olanzapin och risperidon. Quetiapin orsakar, i likhet med haloperidol, mindre viktökning.

    På grund av detta faktum, forskar man numera kring orsakerna till denna skillnad för att förbättra biverkningsprofilen hos framtida antipsykotika.

    2008:F2

  • 7. Abdallah, Qasem M. A.
    et al.
    Phillips, Roger M.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cosentino, Laura
    Abdel-Rahman, Hamdy
    Etzad, Jasarat
    Wheelhouse, Richard T.
    Kiakos, Konstantinos
    Bingham, John P.
    Hartley, John A.
    Patterson, Laurence H.
    Pors, Klaus
    Minor structural modifications to alchemix influence mechanism of action and pharmacological activity2012In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 83, no 11, p. 1514-1522Article in journal (Refereed)
    Abstract [en]

    Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

  • 8.
    Abdel Rehim, Abbi
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Abdel Rehim, Mohamed
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Screening and determination of drugs in human saliva utilizing microextraction by packed sorbent and liquid chromatography-tandem mass spectrometry2013In: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 27, no 9, p. 1188-1191Article in journal (Refereed)
    Abstract [en]

    This study presents a new method for collecting and handling saliva samples using an automated analytical microsyringe and microextraction by packed syringe (MEPS). The screening and determination of lidocaine in human saliva samples utilizing MEPS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were carried out. An exact volume of saliva could be collected. The MEPS C-8-cartridge could be used for 50 extractions before it was discarded. The extraction recovery was about 60%. The pharmacokinetic curve of lidocaine in saliva using MEPS-LC-MS/MS is reported.

  • 9.
    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.

  • 10.
    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.

  • 11.
    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.

  • 12.
    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.

  • 13.
    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

  • 14.
    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. 

  • 15.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Végvári, Akos
    Clinical Protein Science, Department of Electrical Measurements, Lund University, Lund, Sweden.
    Youssefi, Masoud
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Levi, Michael
    Tripep AB, Huddinge, Sweden .
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Andersson, Elin
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Horal, Peter
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Svennerholm, Bo
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Balzarini, Jan
    Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 16.
    Abramsson-Zetterberg, Lilianne
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Strongly heated carbohydrate-rich food is an overlooked problem in cancer risk evaluation2018In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 121, p. 151-155Article in journal (Refereed)
    Abstract [en]

    A cascade of compounds is produced when foodstuffs are heated at high temperatures but only a few of these compounds have been identified and quantified. In this study data are evaluated regarding differences in the micronucleus frequency of human erythrocytes (fMNs) in peripheral blood (a known biomarker of genotoxicity) in individuals that consumed either high- or low-heated food during a 4-day period. Concomitantly, acrylamide (aa) levels were measured in the food that the participants consumed. The obtained fMNs in this human study are compared with the fMNs in mice after comparable exposure levels of pure aa. The results of this comparison showed several hundred times higher fMNs in humans compared with mice. With an assumed linear correlation between an increased genotoxic effect and cancer, our data suggest that aa only represents a fraction of all carcinogenic compounds produced in heated carbohydrate-rich food. Consequently, our daily intake of carbohydrate-rich food heated at high temperatures might be responsible for one-fifth of the rate of the total cancer risk. One sentence summary: A biomarker of genotoxicity indicates the risk of cancer to be some hundred-fold greater in heated carbohydrate-rich food than the risk calculated from animal studies on pure acrylamide.

  • 17.
    Abramsson-Zetterberg, Lilianne
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ilback, Nils-Gunnar
    The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo2013In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 59, p. 86-89Article in journal (Refereed)
    Abstract [en]

    The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic.

  • 18.
    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.

  • 19.
    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.

  • 20.
    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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  • 21.
    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)
  • 22. 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.

  • 23.
    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.

  • 24.
    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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    FULLTEXT01
  • 25.
    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.

  • 26.
    Abusabeib, Alyaa
    et al.
    Department of Bariatric Surgery/Bariatric Medicine, Hamad General Hospital, Doha, Qatar.
    El Ansari, Walid
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Department of Surgery, Hamad General Hospital, Doha, Qatar / College of Medicine, Qatar University, Doha, Qatar.
    Alobaidan, Jassim
    Department of Bariatric Surgery/Bariatric Medicine, Hamad General Hospital, Doha, Qatar.
    Elhag, Wahiba
    Department of Bariatric Surgery/Bariatric Medicine, Hamad General Hospital, Doha, Qatar.
    First Case Report of Fulminant Hepatitis After Laparoscopic Sleeve Gastrectomy Associated with Concomitant Maximal Therapeutic Dose of Acetaminophen Use, Protein Calorie Malnutrition, and Vitamins A and D, Selenium, and Glutathione Deficiencies2021In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 31, no 2, p. 899-903Article in journal (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is increasingly being linked to obesity. Although laparoscopic sleeve gastrectomy (LSG) is effective for weight loss that can ultimately resolve NAFLD, an initial transient deterioration of liver functions could be observed during the first few months post-operatively, after which a subsequent improvement of the liver functions might occur. Rapid weight loss, nutritional deficiencies, and protein malnutrition can all contribute to hepatic dysfunction and can affect the metabolism of medications such as acetaminophen leading to more insult to a compromised liver. We report acute liver failure after LSG associated with protein calorie malnutrition, multiple nutritional deficiencies in addition to concomitant use of therapeutic doses of acetaminophen. Treatment with N-acetylcysteine, and replacement of deficient multivitamins and trace elements resulted in significant improvement in liver functions. 

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  • 27.
    Adawi, Rahim
    University of Skövde, School of Engineering Science.
    Preventing fatal effects of overworking: Product design solution2018Independent thesis Basic level (university diploma), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    “Overworking to death” is a phenomenon that has been noticeable in developing countries. The cause of death is mainly through ischemic strokes. While the victims’ occupations differed, they all shared a common characteristic, being positioned in a sedentary work, ranging from IT workers to doctors. This project’s aim was to develop a product that prevented or decreased the strokes that derived from sedentary overwork. This was mainly tackled by preventing one of the three causes of developing blood props, slowed blood flow. In order to gather rich data of the phenomenon, a qualitative study was conducted in China, during two months. By doing an extensive structured sampling, information rich data could be gathered during a short period of time. Data were derived from observations, questionnaires and an interview, which then was interpreted to customer needs and the final product specification. The final product became a trouser with an in built dynamic compression mechanic, that can compress the veins mostly during sitting activities, in order to prevent blood stasis. The compression mechanic works like the Chinese finger trap; compressing the calves while sitting and stretching the legs forward. It is made only out of polysaccharides fibres; cotton and corn.

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    PREVENTING FATAL EFFECTS OF OVERWORKING – PRODUCT DESIGN SOLUTION / Rahim_Adawi
  • 28. 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.

  • 29.
    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.

  • 30. 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)
  • 31.
    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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  • 32. Agathokleous, E.
    et al.
    Barceló, D.
    Aschner, M.
    Azevedo, R. A.
    Bhattacharya, Prosun
    KTH, School of Architecture and the Built Environment (ABE), Sustainable development, Environmental science and Engineering, Water and Environmental Engineering.
    Costantini, D.
    Cutler, G. C.
    De Marco, A.
    Docea, A. O.
    Dórea, J. G.
    Duke, S. O.
    Efferth, T.
    Fatta-Kassinos, D.
    Fotopoulos, V.
    Ginebreda, A.
    Guedes, R. N. C.
    Hayes, A. W.
    Iavicoli, I.
    Kalantzi, O. -I
    Koike, T.
    Kouretas, D.
    Kumar, M.
    Manautou, J. E.
    Moore, M. N.
    Paoletti, E.
    Peñuelas, J.
    Picó, Y.
    Reiter, R. J.
    Rezaee, R.
    Rinklebe, J.
    Rocha-Santos, T.
    Sicard, P.
    Sonne, C.
    Teaf, C.
    Tsatsakis, A.
    Vardavas, A. I.
    Wang, W.
    Zeng, E. Y.
    Calabrese, E. J.
    Rethinking Subthreshold Effects in Regulatory Chemical Risk Assessments2022In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 56, no 16, p. 11095-11099Article in journal (Refereed)
  • 33. 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.

  • 34.
    Aggett, Peter
    et al.
    Lancashire School of Health and Postgraduate Medicine, University of Central Lancashire, Preston, United Kingdom.
    Nordberg, Gunnar F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Nordberg, Monica
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Essential metals: assessing risks from deficiency and toxicity2022In: Handbook on the toxicology of metals: volume I: general considerations / [ed] Gunnar F. Nordberg; Max Costa, London: Academic Press, 2022, 5, p. 385-406Chapter in book (Refereed)
    Abstract [en]

    Recommendations aimed at protecting the public from toxicity of essential elements including essential metals have usually been developed separately from those recommendations aimed at protection from deficiency. Because of the uncertainties involved in the evaluations, these recommendations have sometimes been in conflict, emphasizing the need for a new approach, including a balanced consideration of nutritional and toxicological data. In developing these new principles of evaluation, some basic concepts based on interindividual variability in sensitivity to deficiency and toxicity must be considered. Such variation translates into one interval of (low) daily intakes, at which there is a risk of developing deficiency, and another interval of (high) dietary intakes at which toxicity may occur. In most instances, there is a third set of intakes in between, which represents the acceptable range of oral intake (AROI), in which no adverse effects occur. This range determined from a homeostatic or biologically based (BBM) approach, which is discussed here, would be expected to apply to the general population. It must be noted, however, that this range would not protect all persons from adverse effects: this applies to those with genetically determined sensitivity, who may require higher intakes to avoid deficiency or lower intakes to avoid toxicity than those defined by the AROI. Nonetheless, AROI could be derived to protect 95% of the general human population from minimal adverse effects of deficiency or toxicity arising from inadequate and excessive intakes. As such the correspondence of these values to current Health-Based Guidance Values (HBGVs) and reference intakes of essential metals (EMs), and the roles of the BBM/Homeostatic Approach in Risk Assessment of EMs are of important public health interest.

  • 35.
    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.

  • 36.
    Ahlenius, Sven
    et al.
    Göteborgs universitet.
    Heimann, Mikael
    Göteborgs universitet.
    Larsson, Knut
    Göteborgs universitet.
    Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine.1979In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 65, no 2, p. 137-140Article in journal (Refereed)
    Abstract [en]

    Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.

  • 37.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Frick, Anna
    State Alaska Dept Hlth & Social Serv, AK USA.
    Pongratz, Catherine
    State Alaska Dept Hlth & Social Serv, AK USA.
    Spink, Kimberly
    State Alaska Dept Hlth & Social Serv, AK USA.
    Xavier, Catherine
    State Alaska Dept Hlth & Social Serv, AK USA.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Council, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Genomic comparison of carbapenem-resistant Enterobacteriaceae from humans and gulls in Alaska2021In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 25, p. 23-25Article in journal (Refereed)
    Abstract [en]

    Objectives: Wildlife may harbour clinically important antimicrobial-resistant bacteria, but the role of wildlife in the epidemiology of antimicrobial-resistant bacterial infections in humans is largely unknown. In this study, we aimed to assess dissemination of the bla(KPC) carbapenemase gene among humans and gulls in Alaska. Methods: We performed whole-genome sequencing to determine the genetic context of bla(KPC) in bacterial isolates from all four human carbapenemase-producing Enterobacteriaceae (CPE) infections reported in Alaska between 2013-2018 and to compare the sequences with seven previously reported CPE isolates from gull faeces within the same region and time period. Results: Genomic analysis of CPE isolates suggested independent acquisition events among humans with no evidence for direct transmission of bla(KPC) between people and gulls. However, some isolates shared conserved genetic elements surrounding bla(KPC), suggesting possible exchange between species. Conclusion: Our results highlight the genomic plasticity associated with bla(KPC) and demonstrate that sampling of wildlife may be useful for identifying clinically relevant antimicrobial resistance not observed through local passive surveillance in humans. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

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  • 38.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK USA; US Geol Survey, AK 99508 USA.
    Scott, Laura C.
    US Geol Survey, AK USA.
    Woksepp, Hanna
    Reg Kalmar Cty, Sweden; Linnaeus Univ, Sweden.
    Bonnedahl, Jonas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Reg Kalmar Cty, Sweden.
    Ramey, Andrew M.
    US Geol Survey, AK USA.
    Environmental antimicrobial resistance gene detection from wild bird habitats using two methods: A commercially available culture-independent qPCR assay and culture of indicator bacteria followed by whole-genome sequencing2023In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 33, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Objectives: A variety of methods have been developed to detect antimicrobial resistance (AMR) in differ-ent environments to better understand the evolution and dissemination of this public health threat. Com-parisons of results generated using different AMR detection methods, such as quantitative PCR (qPCR) and whole-genome sequencing (WGS), are often imperfect, and few studies have analysed samples in parallel to evaluate differences. In this study, we compared bacterial culture and WGS to a culture-independent commercially available qPCR assay to evaluate the concordance between methods and the utility of each in answering research questions regarding the presence and epidemiology of AMR in wild bird habitats.Methods: We first assessed AMR gene detection using qPCR in 45 bacterial isolates from which we had existing WGS data. We then analysed 52 wild bird faecal samples and 9 spatiotemporally collected water samples using culture-independent qPCR and WGS of phenotypically resistant indicator bacterial isolates.Results: Overall concordance was strong between qPCR and WGS of bacterial isolates, although concor-dance differed among antibiotic classes. Analysis of wild bird faecal and water samples revealed that more samples were determined to be positive for AMR via qPCR than via culture and WGS of bacterial isolates, although qPCR did not detect AMR genes in two samples from which phenotypically resistant isolates were found.Conclusions: Both qPCR and culture followed by sequencing may be effective approaches for characteris-ing AMR genes harboured by wild birds, although data streams produced using these different tools may have advantages and disadvantages that should be considered given the application and sample matrix.Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

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  • 39.
    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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  • 40.
    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)
  • 41. Aitio, Antero
    et al.
    Bernard, Alfred
    Fowler, Bruce A.
    Nordberg, Gunnar F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Environmental Medicine.
    Biological Monitoring and Biomarkers2007In: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, p. 65-78Chapter in book (Other academic)
    Abstract [en]

    Biomonitoring was developed for the assessment of the health risks from exposure to metals at work, and the approaches and concepts of biomonitoring are derived from such exposures. At present, biomonitoring is increasingly used to assess exposure from the environment. Biomonitoring and assessment of external exposure are complementing activities, where the exposure assessments are much more widely applied, especially when the number of chemicals concerned is considered; environmental analysis also offers the distinct advantage of speciation analysis, which is very poorly developed for biomonitoring. Biomonitoring, on the other hand, provides information on exposure from all sources, and via all absorption routes, and also considers accumulation of the chemical in the body. Biomonitoring using exposure biomarkers thus considers interindividual differences in the absorption, whereas use of effect biomarkers also considers interindividual differences in sensitivity. Few effect biomarkers, however, have been validated. Biomarkers of susceptibility have so far not been adapted for use in metal toxicology. The major challenges of biomonitoring are the development of monitoring methods, which are inexpensive enough to be applied at a frequency that makes possible meaningful biomonitoring of metals with a short half-time; development of exposure biomarker guidance values specific to individual species of different metals; expansion of the repertoire of validated effect biomarkers; and validation and application to effect monitoring of the "omic" technologies.

  • 42.
    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.

  • 43. 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.

  • 44.
    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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  • 45.
    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, 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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  • 46.
    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)
  • 47. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. Swedish Toxicology Sciences Research Center (Swetox), Sweden.
    Andersson, Patrik L.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, p. 164-173Article in journal (Refereed)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 48. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Bergman, Åke
    Andersson, Patrik L
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, p. 164-173Article in journal (Refereed)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 49.
    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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  • 50.
    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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