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  • 1.
    Alexandraki, Krystallenia I.
    et al.
    National and Kapodistrian University of Athens, Athens, Greece; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece.
    Daskalakis, Kosmas
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. National and Kapodistrian University of Athens, Athens, Greece; Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece.
    Tsoli, Marina
    National and Kapodistrian University of Athens, Athens, Greece; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece.
    Grossman, Ashley B
    National and Kapodistrian University of Athens, Athens, Greece; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece.
    Kaltsas, Gregory A.
    National and Kapodistrian University of Athens, Athens, Greece; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece.
    Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)2020Inngår i: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 31, nr 3, s. 239-255Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.

  • 2.
    Andersson, Sören
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Folkhälsomyndigheten, Public Health Agency of Sweden.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    CHIMERIC MOMP ANTIGEN2015Patent (Annet (populærvitenskap, debatt, mm))
    Fulltekst (pdf)
    Patent
  • 3.
    Bansal, Ruby
    et al.
    Biology Department, University of Massachusetts Amherst, Amherst, USA.
    Zoeller, R. Thomas
    Biology Department, University of Massachusetts Amherst, Amherst, USA.
    CLARITY-BPA: Bisphenol A or Propylthiouracil on Thyroid Function and Effects in the Developing Male and Female Rat Brain2019Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 160, nr 8, s. 1771-1785Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The CLARITY-BPA experiment, a large collaboration between the National Institute of Environmental Health Sciences, the National Toxicology Program, and the US Food and Drug Administration, is designed to test the effects of bisphenol A (BPA) on a variety of endocrine systems and end points. The specific aim of this subproject was to test the effect of BPA exposure on thyroid functions and thyroid hormone action in the developing brain. Timed-pregnant National Center for Toxicological Research Sprague-Dawley rats (strain code 23) were dosed by gavage with vehicle control (0.3% carboxymethylcellulose) or one of five doses of BPA [2.5, 25, 250, 2500, or 25,000 µg/kg body weight (bw) per day] or ethinyl estradiol (EE) at 0.05 or 0.50 µg/kg bw/d (n = 8 for each group) beginning on gestational day 6. Beginning on postnatal day (PND) 1 (day of birth is PND 0), the pups were directly gavaged with the same dose of vehicle, BPA, or EE. We also obtained a group of animals treated with 3 ppm propylthiouracil in the drinking water and an equal number of concordant controls. Neither BPA nor EE affected serum thyroid hormones or thyroid hormone‒sensitive end points in the developing brain at PND 15. In contrast, propylthiouracil (PTU) reduced serum T4 to the expected degree (80% reduction) and elevated serum TSH. Few effects of PTU were observed in the male brain and none in the female brain. As a result, it is difficult to interpret the negative effects of BPA on the thyroid in this rat strain because the thyroid system appears to respond differently from that of other rat strains.

  • 4.
    Cao, Huiming
    et al.
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Zhou, Zhen
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Key Laboratory of Optoelectronic Chemical Materials and Devices, Ministry of Education, School of Chemical and Environmental Engineering, Jianghan University, Wuhan, P. R. China.
    Wang, Ling
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Liu, Guangliang
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Sun, Yuzhen
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Wang, Yawei
    Institute of Environment and Health, Jianghan University, Wuhan, P. R. China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, P. R. China.
    Wang, Thanh
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Liang, Yong
    Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Jianghan University, Wuhan, P. R. China; Institute of Environment and Health, Jianghan University, Wuhan, P. R. China.
    Screening of Potential PFOS Alternatives To Decrease Liver Bioaccumulation: Experimental and Computational Approaches2019Inngår i: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 53, nr 5, s. 2811-2819Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Perfluorooctanesulfonate (PFOS) is a persistent organic pollutant with significant bioaccumulation potential in liver tissues. Exposure to PFOS could cause increase of liver weight, induce adenomas of the liver, and cause hepatomegaly. Alternatives of PFOS might be designed and synthesized that have significantly lower liver bioaccumulation. In this study, we conducted animal exposure experiments to investigate tissue accumulations of 14 per- and polyfluoroalkyl substances. Correlation analysis demonstrated that accumulation of the compounds in rat liver had strong correlations with their binding affinities of liver fatty acid binding protein (LFABP). Thus, we combined a quantitative structure-activity relationship model with molecular dynamics (MD) simulations to develop computational models to predict the LFABP binding affinities of two newly synthesized alternatives, perfluorodecalin-2-sulfonic acid and N-diperfluorobutanoic acid. The binding characteristics of the PFOS alternatives for LFABP were elaborated to explore how the different structural modifications of molecules influenced the underlying binding mechanisms. Subsequent animal experiments demonstrated that the binding free energy calculations based on the MD simulations provided a good indicator to reflect the relative degree of liver accumulation of the PFOS alternatives in the same exposure doses and durations. Our findings from the combination of experimental exposure and computational model can provide helpful information to design potential alternatives of PFOS with weak LFABP binding capability and low liver accumulation.

  • 5.
    Connolly, Kristie L.
    et al.
    Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
    Eakin, Ann E.
    Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States.
    Gomez, Carolina
    Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
    Osborn, Blaire L.
    Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States.
    Unemo, Magnus
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology.
    Jerse, Ann E.
    Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States .
    Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model2019Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, nr 3, artikkel-id e01644-18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is a pressing need for drug development for gonorrhea. Here we describe pharmacokinetics/pharmacodynamics (PK/PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. PK determined in uninfected mice displayed a clear dose response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESCS strain FA1090 were 5 mg/kg (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (time of free drug above the MIC, fTMIC) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against the ESCR strain H041. However, fractionation (TIDq8h) of a 120 mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤ 50% of mice with therapeutic times estimated from single-dose PK data, of 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships in mice reflected that observed in humans with in vivo efficacy against an ESCS strain requiring doses that yielded an fTMIC in excess of 20-24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCR strain and were useful in designing effective dosing regimens.

  • 6.
    Eberhardson, M.
    et al.
    Danderyd's Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Söderling, J. K.
    Karolinska Institutet, Stockholm, Sweden.
    Neovius, M.
    Karolinska Institutet, Stockholm, Sweden.
    Cars, T.
    Public Healthcare Service, Stockholm, Sweden; Uppsala University, Uppsala, Sweden.
    Myrelid, P.
    Linköping University, Linköping, Sweden; County Council of Östergötland, Linköping, Sweden.
    Ludvigsson, Jonas F.
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Karolinska Institutet, Stockholm, Sweden.
    Askling, J.
    Karolinska Institutet, Stockholm, Sweden.
    Ekbom, A.
    Karolinska Institutet, Stockholm, Sweden.
    Olén, O.
    Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Stockholm, Sweden.
    Anti-TNF treatment in Crohn's disease and risk of bowel resection-a population based cohort study2017Inngår i: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 46, nr 6, s. 589-598Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: TNF inhibitors (TNFi) have been shown to reduce the need for surgery in Crohn's disease, but few studies have examined their effect beyond the first year of treatment.

    Aim: To conduct a register-based observational cohort study in Sweden 2006-2014 to investigate the risk of bowel resection in bowel surgery naive TNFi-treated Crohn's disease patients and whether patients on TNFi >= 12 months are less likely to undergo bowel resection than patients discontinuing treatment before 12 months.

    Methods: We identified all individuals in Sweden with Crohn's disease through the Swedish National Patient Register 1987-2014 and evaluated the incidence of bowel resection after first ever dispensation of adalimumab or infliximab from 2006 and up to 7 years follow-up.

    Results: We identified 1856 Crohn's disease patients who had received TNFi. Among these patients, 90% treatment retention was observed at 6 months after start of TNFi and 65% remained on the drug after 12 months. The cumulative rates of surgery in Crohn's disease patients exposed to TNFi years 1-7 were 7%, 13%, 17%, 20%, 23%, 25% and 28%. Rates of bowel resection were similar between patients with TNFi survival < 12 months and >= 12 months respectively (P=.27). No predictors (eg, sex, age, extension or duration of disease) for bowel resection were identified.

    Conclusions: The risk of bowel resection after start of anti-TNF treatment is higher in regular health care than in published RCTs. Patients on sustained TNFi treatment beyond 12 months have bowel resection rates similar to those who discontinue TNFi treatment earlier.

  • 7.
    Eklund, Martin
    et al.
    Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; AstraZeneca Research and Development, Mölndal, Sweden.
    Norinder, Ulf
    Lundbeck Corporation, Valby, Denmark.
    Boyer, Scott
    AstraZeneca Research and Development, Mölndal, Sweden.
    Carlsson, Lars
    AstraZeneca Research and Development, Mölndal, Sweden.
    The application of conformal prediction to the drug discovery process2015Inngår i: Annals of Mathematics and Artificial Intelligence, ISSN 1012-2443, E-ISSN 1573-7470, Vol. 74, nr 1-2, s. 117-132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    QSAR modeling is a method for predicting properties, e.g. the solubility or toxicity, of chemical compounds using machine learning techniques. QSAR is in widespread use within the pharmaceutical industry to prioritize compounds for experimental testing or to alert for potential toxicity during the drug discovery process. However, the confidence or reliability of predictions from a QSAR model are difficult to accurately assess. We frame the application of QSAR to preclinical drug development in an off-line inductive conformal prediction framework and apply it prospectively to historical data collected from four different assays within AstraZeneca over a time course of about five years. The results indicate weakened validity of the conformal predictor due to violations of the randomness assumption. The validity can be strengthen by adopting semi-off-line conformal prediction. The non-randomness of the data prevents exactly valid predictions but comparisons to the results of a traditional QSAR procedure applied to the same data indicate that conformal predictions are highly useful in the drug discovery process.

  • 8.
    Eriksson, Leif A.
    et al.
    Göteborgs universitet, Göteborg.
    Sirsjö, Allan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Strid, Åke
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Tetrazole derivatives as cytochrome p450 inhibitors2019Patent (Annet (populærvitenskap, debatt, mm))
    Abstract [en]

    According to the invention there is provided a compound of formula I, wherein Rand Rhave meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.

    Fulltekst (pdf)
    Patent
  • 9.
    Geng, Dawei
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Musse, Ayan Au
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Wigh, Viktoria
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Carlsson, Cecilia
    School of Science and Technology, Örebro University, Örebro, Sweden.
    Engwall, Magnus
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
    Scherbak, Nikolai
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo2019Inngår i: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 170, s. 691-698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Perfluorooctanesulfonate (PFOS) is a well-known contaminant in the environment and it has shown to disrupt multiple biological pathways, particularly those related with lipid metabolism. In this study, we have studied the impact of in ovo exposure to PFOS on lipid metabolism in livers in developing chicken embryos using lipidomics for detailed characterization of the liver lipidome. We used an avian model (Gallus gallus domesticus) for in ovo treatment at two levels of PFOS. The lipid profile of the liver of the embryo was investigated by ultra-high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry and by gas chromatography mass spectrometry. Over 170 lipids were identified, covering phospholipids, ceramides, di- and triacylglycerols, cholesterol esters and fatty acid composition of the lipids. The PFOS exposure caused dose dependent changes in the lipid levels, which included upregulation of specific phospholipids associated with the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, triacylglycerols with low carbon number and double bond count as well as of lipotoxic ceramides and diacylglycerols. Our data suggest that at lower levels of exposure, mitochondrial fatty acid β-oxidation is suppressed while the peroxisomal fatty acid β -oxidation is increased. At higher doses, however, both β -oxidation pathways are upregulated.

  • 10. Hu, Baihua
    et al.
    Collini, Michael
    Unwalla, Rayomand
    Miller, Christopher
    Singhaus, Robert
    Quinet, Elaine
    Savio, Dawn
    Halpern, Anita
    Basso, Michael
    Keith, James
    Clerin, Valerie
    Chen, Liang
    Resmini, Christine
    Liu, Qiang-Yuan
    Feingold, Irene
    Huselton, Christine
    Azam, Farooq
    Farnegardh, Mathias
    Enroth, Cristofer
    Örebro universitet, Institutionen för naturvetenskap.
    Bonn, Tomas
    Goos-Nilsson, Annika
    Wilhelmsson, Anna
    Nambi, Ponnal
    Wrobel, Jay
    Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis2006Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 49, nr 21, s. 6151-6154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRâ and LXRR and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.

  • 11.
    Kadi, Fawzi
    Örebro universitet, Hälsoakademin.
    Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle: a basis for illegal performance enhancement2008Inngår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 154, nr 3, s. 522-528Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The popularity of testosterone among drug users is due to its powerful effects on muscle strength and mass. Important mechanisms behind the myotrophic effects of testosterone were uncovered both in athletes using steroids for several years and in short-term controlled studies. Both long-term and short-term steroid usage accentuates the degree of fibre hypertrophy in human skeletal muscle by enhancing protein synthesis. A mechanism by which testosterone facilitates the hypertrophy of muscle fibres is the activation of satellite cells and the promotion of myonuclear accretion when existing myonuclei become unable to sustain further enhancement of protein synthesis. Interestingly, long-term steroid usage also enhances the frequency of fibres with centrally located myonuclei, which implies the occurrence of a high regenerative activity. Under the action of testosterone, some daughter cells generated by satellite cell proliferation may escape differentiation and return to quiescence, which help to replenish the satellite cell reserve pool. However, whether long-term steroid usage induces adverse effects of satellite cells remains unknown. Testosterone might also favour the commitment of pluripotent precursor cells into myotubes and inhibit adipogenic differentiation. The effects of testosterone on skeletal muscle are thought to be mediated via androgen receptors expressed in myonuclei and satellite cells. Some evidence also suggests the existence of an androgen-receptor-independent pathway. Clearly, testosterone abuse is associated with an intense recruitment of multiple myogenic pathways. This provides an unfair advantage over non-drug users. The long-term consequences on the regenerative capacity of skeletal muscle are unknown.

  • 12. Karypidis, A.-H.
    et al.
    Olsson, M.
    Andersson, Swen-Olof
    Örebro universitet, Hälsoakademin.
    Rane, A.
    Ekström, L.
    Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate2008Inngår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 8, nr 2, s. 147-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metabolism of androgens includes glucuronidation, the major pathway of steroid elimination in several steroid target tissues. Glucuronidation is catalysed by UDP-glucuronosyltransferases (UGTs). UGT2B17 has been shown to be particularly active against androgens and is highly abundant in the prostate. Recently, we discovered that deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. Here, we determined the phenotypic outcome of the deletion by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally, the frequency of UGT2B17 deletion polymorphism was studied in a Swedish population-based case–control study including 176 patients diagnosed with prostate cancer and 161 controls. We found that the individuals homozygous for the insertion allele expressed 30 times more UGT2B17 mRNA in prostate tissue than the heterozygotes. Carriers of the deletion allele had a significantly increased risk of prostate cancer (OR=2.07; 95% CI=1.32–3.25). In conclusion, these results show the UGT2B17 deletion polymorphism is associated with prostate cancer risk. 

  • 13.
    Lindh, Martin
    et al.
    Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    Karlen, Anders
    Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    Norinder, Ulf
    Swetox, Karolinska Institute, Unit of Toxicology Sciences, Södertälje, Sweden; Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
    Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework2017Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, nr 5, s. 1571-1576Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Skin serves as a drug administration route, and skin permeability of chemicals is of significant interest in the pharmaceutical and cosmetic industries. An aggregated conformal prediction (ACP) framework was used to build models, for predicting the permeation rate (log K-p) of chemical compounds through human skin. The conformal prediction method gives as an output the prediction range at a given level of confidence for each compound, which enables the user to make a more informed decision when, for example, suggesting the next compound to prepare, Predictive models were built using;both the random forest and the support vector machine methods and were based on experimentally derived permeability data on 211 diverse compounds. The derived models were of similar predictive quality as compared to earlier published models but have the extra advantage of not only presenting a single predicted value for each, compound but also a reliable, individually assigned prediction range. The models use calculated descriptors and can quickly predict the skin permeation rate of new compounds.

  • 14.
    Ludvigsson, Jonas F.
    et al.
    Örebro universitet, Hälsoakademin.
    Michaelsson, K.
    Ekbom, A.
    Montgomery, Scott M.
    Örebro universitet, Hälsoakademin.
    Coeliac disease and the risk of fractures: a general population-based cohort study2007Inngår i: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 25, nr 3, s. 273-285Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: Earlier studies have suggested that untreated coeliac disease may be associated with osteoporosis, but results are contradictory for the risk of long-term fractures.Aim: To study the association between coeliac disease and fractures.Methods: We used Cox regresson to examine the future risk of hip fracture and fracture of any type in more than 13 000 individuals with coeliac disease and 65 000 age- and sex-matched reference individuals in a general population-based cohort.Results: During follow-up, 1365 first hip fractures and 4847 fractures of any type occurred. Coeliac disease was positively associated with subsequent hip fracture (hazard ratio = 2.1; 95% CI = 1.8-2.4) (in children: hazard ratio = 2.6; 95% CI = 1.1-6.2) and fractures of any type (hazard ratio = 1.4; 95% CI = 1.3-1.5) (in children: hazard ratio = 1.1; 95% CI = 1.0-1.2). The absolute excess risk of hip fractures in children with coeliac disease was 4/100 000 person-years. Incidence ratios for hip fracture in individuals with CD were around two both prior to diagnosis of coeliac disease and afterwards; this risk increase remained 20 years after diagnosis of coeliac disease.Conclusions: Individuals with coeliac disease, including children with coeliac disease, may be at increased risk of hip fracture and fracture of any type. Coeliac disease may be positively associated with long-term hip fracture risk.

  • 15.
    Ludvigsson, Jonas F.
    et al.
    Örebro universitet, Hälsoakademin.
    Olsson, T.
    Ekbom, A.
    Montgomery, Scott M.
    Örebro universitet, Hälsoakademin.
    A population-based study of coeliac disease, neurodegenerative and neuroinflammatory diseases2007Inngår i: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 25, nr 11, s. 1317-1327Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    It has been suggested that coeliac disease (CD) is associated with several neurological diseases. However, the evidence of such an association is inconclusive as earlier research has often been based on small numbers with retrospective data collection.

    Aim

    To use Cox regression to examine the risk of neurological disease in individuals with CD.

    Methods

    Through Swedish national registers we identified some 14 000 individuals with a diagnosis of CD (1964–2003) and 70 000 reference individuals matched for age, sex, calendar year and county.

    Results

    Coeliac disease was associated with later polyneuropathy [hazard ratio (HR) = 3.4; 95% CI = 2.3–5.1]. We found no statistically significant association between CD and subsequent multiple sclerosis (HR = 0.9; 95% CI = 0.3–2.3), Parkinson’s disease (HR = 1.2; 95% CI = 0.8–1.9), Alzheimer’s disease (HR = 1.5; 95% CI = 0.9–2.6), hereditary ataxia (HR = 1.3; 95% CI = 0.5–3.6), the symptom ataxia (HR = 1.9; 95% CI = 0.6–6.2), Huntington’s disease (HR = 1.7; 95% CI = 0.3–8.6), myasthenia gravis (HR = 0.8; 95% CI = 0.2–3.8) or spinal muscular atrophy (HR = 0.5; 95% CI = 0.1–3.8). Prior polyneuropathy was associated with subsequent CD (odds ratio = 5.4; 95% CI = 3.6–8.2).

    Conclusions

    The association between CD and polyneuropathy indicates shared risks. We suggest that individuals with polyneuropathy routinely undergo screening for CD. There is no notable association between CD and other neurological outcomes investigated in this study.

  • 16.
    Norinder, Ulf
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Tuck, Astrud
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Norgren, Kalle
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Munic Kos, Vesna
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Existing highly accumulating lysosomotropic drugs with potential for repurposing to target COVID-192020Inngår i: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 130, artikkel-id 110582Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Given the speed of viral infection spread, repurposing of existing drugs has been given the highest priority in combating the ongoing COVID-19 pandemic. Only drugs that are already registered or close to registration, and therefore have passed lengthy safety assessments, have a chance to be tested in clinical trials and reach patients quickly enough to help in the current disease outbreak.

    Here, we have reviewed available evidence and possible ways forward to identify already existing pharmaceuticals displaying modest broad-spectrum antiviral activity which is likely linked to their high accumulation in cells. Several well studied examples indicate that these drugs accumulate in lysosomes, endosomes and biological membranes in general, and thereby interfere with endosomal pathway and intracellular membrane trafficking crucial for viral infection. With the aim to identify other lysosomotropic drugs with possible inherent antiviral activity, we have applied a set of clear physicochemical, pharmacokinetic and molecular criteria on 530 existing drugs. In addition to publicly available data, we have also used our in silico model for the prediction of accumulation in lysosomes and endosomes. By this approach we have identified 36 compounds with possible antiviral effects, also against coronaviruses. For 14 of them evidence of broad-spectrum antiviral activity has already been reported, adding support to the value of this approach.

    Presented pros and cons, knowledge gaps and methods to identify lysosomotropic antivirals, can help in the evaluation of many drugs currently in clinical trials considered for repurposing to target COVID-19, as well as open doors to finding more potent and safer alternatives.

  • 17.
    Nyman, Elin
    et al.
    Department of Biomedical Engineering, Linköping University, Linköping, Sweden.
    Lindh, Maria
    Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory & Inflammation, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Lövfors, William
    Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Department of Mathematics, Linköping University, Linköping, Sweden.
    Simonsson, Christian
    Department of Biomedical Engineering, Linköping University, Linköping, Sweden.
    Persson, Alexander
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Eklund, Daniel
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Bäckström, Erica
    Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory & Inflammation, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Fridén, Markus
    Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory & Inflammation, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Cedersund, Gunnar
    Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
    Mechanisms of a sustained anti-inflammatory drug response in alveolar macrophages unraveled with mathematical modeling2020Inngår i: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 9, nr 12, s. 707-717Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g. asthma and atherosclerosis. Anti-inflammatory drugs come with side-effects which may be aggravated by high and fluctuating drug concentrations. To remedy this, an anti-inflammatory drug should have an appropriate pharmacokinetic half-life or better still: a sustained anti-inflammatory drug response. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti-inflammatory response to a common glucocorticoid drug, Dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism - a slow release of Dexamethasone from the receptor-drug complex. The developed model is in agreement with time-resolved training and testing data, and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge-driven drug development, to find sustained anti-inflammatory responses and fewer side effects.

  • 18.
    Ph van Trijp, Mara
    et al.
    Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
    Wilms, Ellen
    Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
    Ríos-Morales, Melany
    Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
    Masclee, Ad Am
    Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
    Brummer, Robert Jan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Witteman, Ben Jm
    Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands; Hospital Gelderse Vallei, Department of Gastroenterology and Hepatology, Ede, The Netherlands.
    Troost, Freddy J.
    Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; Food Innovation and Health, Centre for Healthy Eating and Food Innovation, Maastricht University, Maastricht, The Netherlands.
    Hooiveld, Guido Jej
    Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
    Using naso- and oro-intestinal catheters in physiological research for intestinal delivery and sampling in vivo: practical and technical aspects to be considered2021Inngår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 114, nr 3, s. 843-861Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Intestinal catheters have been used for decades in human nutrition, physiology, pharmacokinetics, and gut microbiome research, facilitating the delivery of compounds directly into the intestinal lumen or the aspiration of intestinal fluids in human subjects. Such research provides insights about (local) dynamic metabolic and other intestinal luminal processes, but working with catheters might pose challenges to biomedical researchers and clinicians. Here, we provide an overview of practical and technical aspects of applying naso- and oro-intestinal catheters for delivery of compounds and sampling luminal fluids from the jejunum, ileum, and colon in vivo. The recent literature was extensively reviewed, and combined with experiences and insights we gained through our own clinical trials. We included 60 studies that involved a total of 720 healthy subjects and 42 patients. Most of the studies investigated multiple intestinal regions (24 studies), followed by studies investigating only the jejunum (21 studies), ileum (13 studies), or colon (2 studies). The ileum and colon used to be relatively inaccessible regions in vivo. Custom-made state-of-the-art catheters are available with numerous options for the design, such as multiple lumina, side holes, and inflatable balloons for catheter progression or isolation of intestinal segments. These allow for multiple controlled sampling and compound delivery options in different intestinal regions. Intestinal catheters were often used for delivery (23 studies), sampling (10 studies), or both (27 studies). Sampling speed decreased with increasing distance from the sampling syringe to the specific intestinal segment (i.e., speed highest in duodenum, lowest in ileum/colon). No serious adverse events were reported in the literature, and a dropout rate of around 10% was found for these types of studies. This review is highly relevant for researchers who are active in various research areas and want to expand their research with the use of intestinal catheters in humans in vivo.

  • 19.
    Saber, Amanj
    et al.
    Department of Clinical Neuroscience, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Laurell, Göran
    Department of Clinical Sciences, Umeå University, Umeå, Sweden.
    Tobias, Bramer
    Department of Pharmacy, Uppsala University, Uppsala, Sweden.
    Katarina, Edsman
    Department of Pharmacy, Uppsala University, Uppsala, Sweden.
    Cecilia, Engmer
    Department of Clinical Neuroscience, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Mats, Ulfendahl
    Department of Clinical Neuroscience, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Middle Ear Application of Hyaluronic Acid Gel Loaded with Neomycin in a Guinea Pig Model2008Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Background: One alternative for controlled drug delivery to the inner ear is application of medication to the middle ear cavity on the promise that it will diffuse through the round window membrane (RWM) into the inner ear.

    Objective: to evaluate the efficacy of hyaluronic acid gel (HYA) as a vehicle for drugs that are aimed to treat inner ear disorders.

    Methods: in this study the cochlear hair cell loss and RWM morphology were investigated after topical application. Neomycin was chosen as tracer for drug release and the ototoxic effect was evaluated. HYA, (0.5%) loaded with 3 different concentrations of neomycin, was injected to the middle ear cavity of guinea pigs. the ototoxic effect of neomycin in HYA gel was compared to that of neomycin solution applied to the middle ear cavity. Phalloidin stained surface preparation of the organ of Corti was used to estimate hair cell loss induced by neomycin. the thickness of the midportion of the RWM was measured and compared with that of controls using light and electrom microscope.

    Result: Neomycin induced a considerable hair cell loss in guinea pigs receiving middle ear injection of HYA loaded with the drug. One week after topical application the thickness of the RWM was dependent upon the concentration of neomycin administered to the middle ear. At 4 weeks the thickness of the RWM had returned to normal.

    Conclusion: HYA is a safe vehicle for drugs aimed to pass into the inner ear through the RWM. Neomycin was released from HYA and transported into the inner ear as evidenced by hair cell loss. Key words: Round window membrane (RWM), hyaluronic acid gel, HYA, hair cell loss, thickness.

  • 20.
    Saber, Amanj
    et al.
    Center for Hearing and Communication Research, and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Otolaryngology, Karolinska University Hospital, Stockholm, Sweden.
    Strand, Sabina P.
    The Norwegian Biopolymer Laboratory NOBIPOL, Department of Biotechnology, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Ulfendahl, Mats
    Center for Hearing and Communication Research, and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Otolaryngology, Karolinska University Hospital, Stockholm, Sweden.
    Use of the biodegradable polymer chitosan as a vehicle for applying drugs to the inner ear2010Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 39, nr 1-3, s. 110-115Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Development of efficient local delivery systems for the auditory organ has an important role in clinical practice for the management of inner ear disorders using pharmacological means. Chitosan, a biodegradable polymer, is a good drug carrier with bioadhesive properties. The aim of this study was to investigate the feasibility of using chitosan to deliver drugs to the inner ear across the round window membrane (RWM). Three structurally different chitosans loaded with a tracer drug, neomycin, were injected into the middle ear cavity of albino guinea pigs (n=35). After 7 days the effect of chitosans and neomycin was compared among the treatment groups. The hearing organ was analysed for hair cell loss and the RWM evaluated in term of thickness. All tested chitosan formulations successfully released the loaded neomycin which then diffused across the RWM, and exerted ototoxic effect on the cochlear hair cells in a degree depending on the concentrations used. Chitosans per se had no noxious effect on the cochlear hair cells. It is concluded that the chitosans, and especially glycosylated derivative, are safe and effective carriers for inner ear therapy.

  • 21.
    Saber, Amanj
    et al.
    Center for Hearing and Communication Research, Karolinska Institute, Stockholm, Sweden; Department of Otolaryngology, Karolinska University Hospital, Stockholm, Sweden.
    Strand, Sabina
    The Norwegian Biopolymer Laboratory (NOBIPOL), Deptartment of Biotechnology, Norwegian University of Science and Technology, Trondheim, Norway.
    Ulfendahl, Mats
    Center for Hearing and Communication Research, Karolinska Institute, Stockholm, Sweden; Department of Otolaryngology, Karolinska University Hospital, Stockholm, Sweden.
    Use of the Biodegradable Polymer Chitosan as a Vehicle for Applying Drugs to the Inner Ear2010Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Development of efficient local delivery systems for the auditory organ has an important role in clinical practice for the management of inner ear disorders using pharmacological means. Chitosan, a biodegradable polymer, is a good drug carrier with bioadhesive properties. The aim of this study was to investigate the feasibility of using chitosan to deliver drugs to the inner ear across the round window membrane (RWM). Three structurally different chitosans loaded with a tracer drug, neomycin, were injected into the middle ear cavity of albino guinea pigs (n=35). After 7 days the effect of chitosans and neomycin was compared among the treatment groups. The hearing organ was analysed for hair cell loss and the RWM evaluated in term of thickness. All tested chitosan formulations successfully released the loaded neomycin which then diffused across the RWM, and exerted ototoxic effect on the cochlear hair cells in a degree depending on the concentrations used. Chitosans per se had no noxious effect on the cochlear hair cells. It is concluded that the chitosans, and especially glycosylated derivative, are safe and effective carriers for inner ear therapy.

  • 22. Saulo, Eleonor C.
    et al.
    Forsberg, Birger C.
    Premji, Zul
    Montgomery, Scott M.
    Örebro universitet, Hälsoakademin.
    Björkman, Anders
    Willingness and ability to pay for artemisinin-based combination therapy in rural Tanzania2008Inngår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 7, s. 227-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to analyse willingness to pay (WTP) and ability to pay (ATP) for ACT for children below five years of age in a rural setting in Tanzania before the introduction of artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria. Socio-economic factors associated with WTP and expectations on anti-malaria drugs, including ACT, were also explored.

    Methods

    Structured interviews and focus group discussions were held with mothers, household heads, health-care workers and village leaders in Ishozi, Gera and Ishunju wards in north-west Tanzania in 2004. Contingent valuation method (CVM) was used with "take-it-or-leave-it" as the eliciting method, expressed as WTP for a full course of ACT for a child and households' opportunity cost of ACT was used to assess ATP. The study included descriptive analyses with multivariate adjustment for potential confounding factors.

    Results

    Among 265 mothers and household heads, 244 (92%, CI = 88%–95%) were willing to pay Tanzanian Shillings (TSh) 500 (US$ 0.46) for a child's dose of ACT, but only 55% (49%–61%) were willing to pay more than TSh 500. Mothers were more often willing to pay than male household heads (adjusted odds ratio = 2.1, CI = 1.2–3.6). Socio-economic status had no significant effect on WTP. The median annual non-subsidized ACT cost for clinical malaria episodes in an average household was calculated as US$ 6.0, which would represent 0.9% of the average total consumption expenditures as estimated from official data in 2001. The cost of non-subsidized ACT represented 7.0% of reported total annual expenditure on food and 33.0% of total annual expenditure on health care.

    "Rapid effect," "no adverse effect" and "inexpensive" were the most desired features of an anti-malarial drug.

    Conclusion

    WTP for ACT in this study was less than its real cost and a subsidy is, therefore, needed to enable its equitable affordability. The decision taken in Tanzania to subsidize Coartem® fully at governmental health care facilities and at a consumer price of TSh 300–500 (US$ 0.28–0.46) at special designated shops through the programme of Accredited Drug Dispensing Outlets (ADDOs) appears to be well founded.

  • 23.
    Snowden, Stuart G.
    et al.
    Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
    Grapov, Dmitry
    NIH West Coast Metabolomics Center, University of California, Davis, United States; Department of Nutrition, University of California, Davis, United States.
    Settergren, Magnus
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    D'Alexandri, Fabio Luiz
    Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
    Haeggström, Jesper Z.
    Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
    Fiehn, Oliver
    NIH West Coast Metabolomics Center, University of California, Davis, United States.
    Hyötyläinen, Tuulia
    Örebro universitet, Institutionen för naturvetenskap och teknik. Department of Bio- and Chemical Processes, VTT Technical Research Centre of Finland, Espoo, Finland; gSteno Diabetes Center A/S, Gentofte, Denmark.
    Pedersen, Theresa L
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Newman, John W.
    Department of Nutrition, University of California, Davis, United States; Obesity and Metabolism Research Unit, USDA-ARS Western Human Nutrition Research Center, Davis CA, United States.
    Oresic, Matej
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Bio- and Chemical Processes, VTT Technical Research Centre of Finland, Espoo, Finland; gSteno Diabetes Center A/S, Gentofte, Denmark.
    Pernow, John
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Wheelock, Craig E.
    Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
    High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin/ezetimibe combination therapy2014Inngår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 7, nr 6, s. 955-964Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0×10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=0.54; cross-validated ANOVA P=2.6×10(-5)). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R(2)Y=0.65; Q(2)=0.61; cross-validated ANOVA P=5.4×10(-8)). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of low-density lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.

  • 24.
    Svensson, Fredrik
    et al.
    Department of Chemistry, University of Cambridge, Cambridge, England.
    Norinder, Ulf
    Karolinska Institute, Unit of Toxicology Sciences, Södertälje, Sweden; Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden.
    Bender, Andreas
    Department of Chemistry, University of Cambridge, Cambridge, England.
    Improving Screening Efficiency through Iterative Screening Using Docking and Conformal Prediction2017Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, nr 3, s. 439-444Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High-throughput screening, where thousands of molecules rapidly can be assessed for activity against a protein, has been the dominating approach in drug discovery for many years. However, these methods are costly and require much time and effort. In order to suggest an improvement to this situation, in this study, we apply an iterative screening process, where an initial set of compounds are selected for screening based on molecular docking. The outcome of the initial screen is then used to classify the remaining compounds through a conformal predictor. The approach was retrospectively validated using 41 targets from the Directory of Useful Decoys, Enhanced (DUD-E), ensuring scaffold diversity among the active compounds. The results show that 57% of the remaining active compounds could be identified while only screening 9.4% of the database. The overall hit rate (7.6%) was also higher than, when using docking alone (5.2%). When limiting the search to the top scored compounds from docking, 39.6% of the active compounds could be identified, compared to 13.5% when screening the same number of compounds solely based on docking. The use of conformal predictors also gives a clear indication of the number of compounds to screen in the next iteration. These results indicate that iterative screening based on molecular docking and conformal prediction can be an efficient way to find active compounds while screening only a small part of the compound collection.

  • 25.
    Winkler, Martin S.
    et al.
    Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Göttingen, Germany.
    Skirecki, Tomasz
    Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education, Warsaw, Poland.
    Brunkhorst, Frank M.
    Dept. of Anesthesiology and Intensive Care Medicine & Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University, Am Klinikum 1, Jena, Germany; Center for Clinical Studies, Jena University Hospital, Jena, Germany.
    Cajander, Sara
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Infectious Diseases.
    Cavaillon, Jean-Marc
    French National Research Agency (ANR), Paris, France.
    Ferrer, Ricard
    Intensive Care Department and Shock, Organ Dysfunction and Resuscitation Research Group, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomedica En Red-Enfermedades Respiratorias (CibeRes, CB06/06/0028), Instituto de salud Carlos III (ISCIII), Madrid, Spain.
    Flohé, Stefanie B.
    Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
    García-Salido, Alberto
    Pediatric Critical Care Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
    Giamarellos-Bourboulis, Evangelos J.
    4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
    Girardis, Massimo
    Department of Anesthesia and Intensive Care, University Hospital of Modena, Italy.
    Kox, Matthijs
    Department of Intensive Care Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
    Lachmann, Gunnar
    Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
    Martin-Loeches, Ignacio
    Multidisciplinary Intensive Care Research Organization (MICRO), St. James's Hospital, James's St N, Ushers, Dublin, Ireland.
    Netea, Mihai G.
    Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
    Spinetti, Thibaud
    Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
    Schefold, Joerg C.
    Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
    Torres, Antoni
    Pneumology Department, Respiratory Institute (ICR), Hospital Clinic of Barcelona - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - University of Barcelona (UB), Spain.
    Uhle, Florian
    Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
    Venet, Fabienne
    Hospices Civils de Lyon, Immunology Laboratory, Edouard Herriot Hospital, Lyon, France; EA 7426 "Pathophysiology of Injury-Induced Immunosuppression - PI3", Université Claude Bernard Lyon 1/bioMérieux/Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.
    Weis, Sebastian
    Dept. of Anesthesiology and Intensive Care Medicine & Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University, Am Klinikum 1, Jena, Germany; Institute for Infectious Disease and Infection Control, Jena University Hospital-Friedrich Schiller University, Am Klinikum 1, Jena, Germany.
    Scherag, André
    Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital-Friedrich Schiller University, Jena, Germany.
    Rubio, Ignacio
    Dept. of Anesthesiology and Intensive Care Medicine & Center for Sepsis Control and Care (CSCC), Jena University Hospital-Friedrich Schiller University, Am Klinikum 1, Jena, Germany.
    Osuchowski, Marcin F.
    Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria.
    Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge2021Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 66, artikkel-id 103291Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

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