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  1. Article ; Conference proceedings: Lessons from TGN-1412 - the impact on phase I clinical trials.

    Weerasekera, Natasha / Hudson, Ian

    IDrugs : the investigational drugs journal

    2007  Volume 10, Issue 4, Page(s) 230–232

    MeSH term(s) Animals ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/toxicity ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/toxicity ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Drug Industry ; Europe ; Humans ; Macaca fascicularis
    Chemical Substances Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; TGN-1412 monoclonal antibody
    Language English
    Publishing date 2007-04
    Publishing country England
    Document type Congresses
    ZDB-ID 2086568-5
    ISSN 2040-3410 ; 1369-7056
    ISSN (online) 2040-3410
    ISSN 1369-7056
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Semi quantitative expression analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C,OATP-D, OATP-E and NTCP gene transcripts in 1st and 3rd trimester human placenta.

    Patel, P / Weerasekera, N / Hitchins, M / Boyd, C A R / Johnston, D G / Williamson, C

    Placenta

    2003  Volume 24, Issue 1, Page(s) 39–44

    Abstract: Using real time RT-PCR, we have detected expression of seven genes that influence bile acid transport,MDR3, FIC1, BSEP, OATP-A, OATP-C, OATP-D and OATP-E, in normal human placenta. With the exception of OATP-C and OATP-E these genes were found to be ... ...

    Abstract Using real time RT-PCR, we have detected expression of seven genes that influence bile acid transport,MDR3, FIC1, BSEP, OATP-A, OATP-C, OATP-D and OATP-E, in normal human placenta. With the exception of OATP-C and OATP-E these genes were found to be differentially expressed in 1st trimester and 3rd trimester placentae. MDR3 gene expression was found to be up regulated four fold in 3rd trimester placentae compared to 1st trimester, OATP-A gene expression was down regulated eight fold, OATP-D was down regulated 17 fold, while FIC1 expression was reduced by 33 fold in the 3rd trimester. OATP-C and BSEP gene expression was not detected in the 3rd trimester placenta, while low levels of transcripts were detected in the 1st trimester placentae. Transcripts of the hepatic sinusoidal bile acid transporter, NTCP, were not detected in placenta.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 11 ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; Adult ; Bile Acids and Salts/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Down-Regulation ; Female ; Gene Expression Regulation, Developmental ; Humans ; Membrane Transport Proteins ; Organic Anion Transporters/genetics ; Organic Anion Transporters/metabolism ; Organic Anion Transporters, Sodium-Dependent ; Placenta/metabolism ; Pregnancy ; Pregnancy Trimester, First ; Pregnancy Trimester, Third ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Symporters ; Transcription, Genetic ; Up-Regulation
    Chemical Substances ABCB11 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 11 ; ATP-Binding Cassette Transporters ; Bile Acids and Salts ; Carrier Proteins ; Membrane Transport Proteins ; Organic Anion Transporters ; Organic Anion Transporters, Sodium-Dependent ; RNA, Messenger ; Symporters ; sodium-bile acid cotransporter (145420-23-1) ; multidrug resistance protein 3 (9EI49ZU76O) ; Adenosine Triphosphatases (EC 3.6.1.-) ; ATP8B1 protein, human (EC 3.6.1.3.)
    Language English
    Publishing date 2003-01
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 603951-0
    ISSN 1532-3102 ; 0143-4004
    ISSN (online) 1532-3102
    ISSN 0143-4004
    DOI 10.1053/plac.2002.0879
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1578: Show issues Location:
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  3. Article: Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.

    Savander, M / Ropponen, A / Avela, K / Weerasekera, N / Cormand, B / Hirvioja, M-L / Riikonen, S / Ylikorkala, O / Lehesjoki, A-E / Williamson, C / Aittomäki, K

    Gut

    2003  Volume 52, Issue 7, Page(s) 1025–1029

    Abstract: Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease.: Patients and ... ...

    Abstract Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease.
    Patients and methods: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3.
    Results: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families.
    Conclusions: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP-Binding Cassette Transporters/genetics ; Adult ; Bile Acids and Salts/blood ; Cholestasis, Intrahepatic/epidemiology ; Cholestasis, Intrahepatic/genetics ; Family Health ; Female ; Finland/epidemiology ; Genes, Dominant/genetics ; Genetic Heterogeneity ; Genetic Linkage/genetics ; Genotype ; Haplotypes/genetics ; Humans ; Incidence ; Pedigree ; Pregnancy ; Pregnancy Complications/epidemiology ; Pregnancy Complications/etiology ; Prospective Studies ; Transaminases/blood
    Chemical Substances ATP Binding Cassette Transporter, Subfamily B ; ATP-Binding Cassette Transporters ; Bile Acids and Salts ; multidrug resistance protein 3 (9EI49ZU76O) ; Transaminases (EC 2.6.1.-)
    Language English
    Publishing date 2003-03-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80128-8
    ISSN 1468-3288 ; 0017-5749
    ISSN (online) 1468-3288
    ISSN 0017-5749
    DOI 10.1136/gut.52.7.1025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy.

    Müllenbach, R / Linton, K J / Wiltshire, S / Weerasekera, N / Chambers, J / Elias, E / Higgins, C F / Johnston, D G / McCarthy, M I / Williamson, C

    Journal of medical genetics

    2003  Volume 40, Issue 5, Page(s) e70

    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP-Binding Cassette Transporters/genetics ; Cholestasis, Intrahepatic/genetics ; DNA Mutational Analysis ; Exons/genetics ; Female ; Gene Frequency/genetics ; Genetic Variation/genetics ; Haplotypes/genetics ; Humans ; Male ; Pedigree ; Pregnancy ; Pregnancy Complications ; United Kingdom
    Chemical Substances ATP Binding Cassette Transporter, Subfamily B ; ATP-Binding Cassette Transporters ; multidrug resistance protein 3 (9EI49ZU76O)
    Language English
    Publishing date 2003-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmg.40.5.e70
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 177: Show issues Location:
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  5. Article: Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking.

    Dixon, P H / Weerasekera, N / Linton, K J / Donaldson, O / Chambers, J / Egginton, E / Weaver, J / Nelson-Piercy, C / de Swiet, M / Warnes, G / Elias, E / Higgins, C F / Johnston, D G / McCarthy, M I / Williamson, C

    Human molecular genetics

    2000  Volume 9, Issue 8, Page(s) 1209–1217

    Abstract: Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy with serious consequences for the mother and fetus. Two pedigrees have been reported with ICP in the mothers of children with a subtype of autosomal recessive progressive ... ...

    Abstract Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy with serious consequences for the mother and fetus. Two pedigrees have been reported with ICP in the mothers of children with a subtype of autosomal recessive progressive familial intrahepatic cholestasis (PFIC) with raised serum gamma-glutamyl transpeptidase (gamma-GT). Affected children have homozygous mutations in the MDR3 gene (also called ABCB4 ), and heterozygous mothers have ICP. More frequently, however, ICP occurs in women with no known family history of PFIC and the genetic basis of this disorder is unknown. We investigated eight women with ICP and raised serum gamma-GT, but with no known family history of PFIC. DNA sequence analysis revealed a C to A transversion in codon 546 in exon 14 of MDR3 in one patient, which results in the missense substitution of the wild-type alanine with an aspartic acid. We performed functional studies of this mutation introduced into MDR1, a closely related homologue of MDR3. Fluorescence activated cell sorting (FACS) and western analysis indicated that this missense mutation causes disruption of protein trafficking with a subsequent lack of functional protein at the cell surface. The demonstration of a heterozygous missense mutation in the MDR3 gene in a patient with ICP with no known family history of PFIC, analysed by functional studies, is a novel finding. This shows that MDR3 mutations are responsible for the additional phenotype of ICP in a subgroup of women with raised gamma-GT.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ; ATP-Binding Cassette Transporters/genetics ; Amino Acid Substitution ; Cell Line ; Child ; Cholestasis, Intrahepatic/genetics ; Codon ; Exons ; Female ; Genes, Recessive ; Heterozygote ; Humans ; Infant, Newborn ; Models, Molecular ; Mutagenesis, Site-Directed ; Mutation, Missense ; Pregnancy ; Pregnancy Complications ; Protein Structure, Secondary ; Transfection ; gamma-Glutamyltransferase/blood
    Chemical Substances ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; ATP-Binding Cassette Transporters ; Codon ; multidrug resistance protein 3 (9EI49ZU76O) ; gamma-Glutamyltransferase (EC 2.3.2.2)
    Language English
    Publishing date 2000-05-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/9.8.1209
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3469: Show issues Location:
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  6. Article: 1,4-benzodiazepines as inhibitors of respiratory syncytial virus. The identification of a clinical candidate.

    Henderson, Elisa A / Alber, Dagmar G / Baxter, Robert C / Bithell, Sian K / Budworth, Joanna / Carter, Malcolm C / Chubb, Ann / Cockerill, G Stuart / Dowdell, Verity C L / Fraser, Ian J / Harris, Robert A / Keegan, Sally J / Kelsey, Richard D / Lumley, James A / Stables, Jeremy N / Weerasekera, Natasha / Wilson, Lara J / Powell, Kenneth L

    Journal of medicinal chemistry

    2007  Volume 50, Issue 7, Page(s) 1685–1692

    Abstract: Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. ... ...

    Abstract Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. Racemic 1,4-benzodiazepines show potent anti-RSV activity in vitro. Anti-RSV evaluation of 3-position R- and S-benzodiazepine enantiomers and subsequent optimization of this series resulted in selection of a clinical candidate. Antiviral activity was found to reside mainly in the S-enantiomer, and the R-enantiomers were consistently less active against RSV. Analogues of 1,4-(S)-benzodiazepine were synthesized as part of the lead optimization program at Arrow and tested in the XTT assay. From this exercise, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-urea, 17b (RSV-604) was identified as a clinical candidate, exhibiting potent anti-RSV activity in the XTT assay, which was confirmed in secondary assays. Compound 17b also possessed a good pharmacokinetic profile and has now progressed into the clinic.
    MeSH term(s) Animals ; Antiviral Agents/chemical synthesis ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Benzodiazepines/chemical synthesis ; Benzodiazepines/pharmacokinetics ; Benzodiazepines/pharmacology ; Benzodiazepinones/chemical synthesis ; Benzodiazepinones/pharmacokinetics ; Benzodiazepinones/pharmacology ; Cell Line, Tumor ; Crystallography, X-Ray ; Dogs ; Enzyme-Linked Immunosorbent Assay ; Humans ; In Vitro Techniques ; Microsomes/metabolism ; Molecular Structure ; Phenylurea Compounds/chemical synthesis ; Phenylurea Compounds/pharmacokinetics ; Phenylurea Compounds/pharmacology ; Rats ; Respiratory Syncytial Viruses/drug effects ; Stereoisomerism ; Structure-Activity Relationship ; Viral Plaque Assay
    Chemical Substances 1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)urea ; Antiviral Agents ; Benzodiazepinones ; Phenylurea Compounds ; Benzodiazepines (12794-10-4)
    Language English
    Publishing date 2007-04-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm060747l
    Database MEDical Literature Analysis and Retrieval System OnLINE

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