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  • 1
    Online Resource
    Online Resource
    Novel Therapies for Metastatic Melanoma: An Update on Their Use in Older Patients
    Springer Science and Business Media LLC ; 2015
    In:  Drugs & Aging Vol. 32, No. 10 ( 2015-10), p. 821-834
    Details
    In: Drugs & Aging, Springer Science and Business Media LLC, Vol. 32, No. 10 ( 2015-10), p. 821-834
    Type of Medium: Online Resource
    ISSN: 1170-229X , 1179-1969
    URL: Article
    DOI: 10.1007/s40266-015-0304-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 2043689-0
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  • 2
    Online Resource
    Online Resource
    Organotypic Epithelial Raft Cultures as a Model for Evaluating Compounds against Alphaherpesviruses
    American Society for Microbiology ; 2005
    In:  Antimicrobial Agents and Chemotherapy Vol. 49, No. 11 ( 2005-11), p. 4671-4680
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 49, No. 11 ( 2005-11), p. 4671-4680
    Abstract: The course of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and varicella-zoster virus (VZV) infections in squamous epithelial cells cultured in a three-dimensional organotypic raft culture was tested. In these raft cultures, normal human keratinocytes isolated from neonatal foreskins grown at the air-liquid interface stratified and differentiated, reproducing a fully differentiated epithelium. Typical cytopathic changes identical to those found in the squamous epithelium in vivo, including ballooning and reticular degeneration with the formation of multinucleate cells, were observed throughout the raft following infection with HSV and VZV at different times after lifting the cultures to the air-liquid interface. For VZV, the aspects of the lesions depended on the stage of differentiation of the organotypic cultures. The activity of reference antiviral agents, acyclovir (ACV), penciclovir (PCV), brivudin (BVDU), foscarnet (PFA), and cidofovir (CDV), was evaluated against wild-type and thymidine kinase (TK) mutants of HSV and VZV in the raft cultures. ACV, PCV, and BVDU protected the epithelium against cytopathic effect induced by wild-type viruses in a concentration-dependent manner, while treatment with CDV and PFA proved protective against the cytodestructive effects induced by both TK + and TK − strains. The quantification of the antiviral effects in the rafts were accomplished by measuring viral titers by plaque assay for HSV and by measuring viral DNA load by real-time PCR for VZV. A correlation between the degree of protection as determined by histological examination and viral quantification could be demonstrated The three-dimensional epithelial raft culture represents a novel model for the study of antiviral agents active against HSV and VZV. Since no animal model is available for the evaluation of antiviral agents against VZV, the organotypic cultures may be considered a model to evaluate the efficacy of new anti-VZV antivirals before clinical trials.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.49.11.4671-4680.2005
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2005
    detail.hit.zdb_id: 1496156-8
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    SSG: 15,3
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  • 3
    Online Resource
    Online Resource
    Activity of the Anti-Orthopoxvirus Compound ST-246 against Vaccinia, Cowpox and Camelpox Viruses in Cell Monolayers and Organotypic Raft Cultures
    SAGE Publications ; 2007
    In:  Antiviral Therapy Vol. 12, No. 8 ( 2007-11), p. 1205-1216
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 12, No. 8 ( 2007-11), p. 1205-1216
    Abstract: The potential use of variola virus as a biological weapon has renewed efforts in the development of antiviral agents against orthopoxviruses. ST-246 [4-trifluoromethyl-W-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop [f]isoindol-2(1H)-yl)-benza-mide] is an anti-orthopoxvirus compound active against several orthopoxviruses including vaccinia virus (VV), cowpox virus (CPV), camelpox virus (CMLV), ectromelia virus (ECTV) and variola virus in cell culture. The compound has been shown to inhibit the release of extracellular virus by targeting the F13L VV protein and to protect mice from VV, CPV and ECTV orthopoxvirus-induced disease. Methods The antiviral activity of ST-246 was assessed against extracellular and intracellular VV, CPV and CMLV production in human embryonic lung (HEL) fibroblasts and primary human keratinocyte (PHK) cell monolayers, as well as in three-dimensional raft cultures. Results ST-246 inhibited preferentially the production of extracellular virus compared with intracellular virus production in HEL and PHK cells (for VV) and in PHK cells (for CMLV). In organotypic epithelial raft cultures, ST-246 at 20 μg/ml inhibited extracellular VV and CMLV production by 6 logs, whereas intracellular virus yield was reduced by 2 logs. In the case of CPV, both extracellular and intracellular virus production were completely inhibited by ST-246 at 20 μg/ml. Histological sections of the infected rafts, treated with increasing amounts of drug, confirmed the antiviral activity of ST-246: the epithelium was protected and there was no evidence of viral infection. Electron microscopic examination confirmed the absence of intracellular enveloped virus forms in VV-, CPV- and CMLV-infected cells treated with 10 μg/ml of ST-246. Conclusions These data indicate that ST-246 is a potent anti-orthopoxvirus compound; the mode of inhibition is dependent on the virus and cell type.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350701200802
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2007
    detail.hit.zdb_id: 2118396-X
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  • 4
    Online Resource
    Online Resource
    Activities of Alkoxyalkyl Esters of Cidofovir (CDV), Cyclic CDV, and ( S )-9-(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenine against Orthopoxviruses in Cell Monolayers and in Organotypic Cultures
    American Society for Microbiology ; 2006
    In:  Antimicrobial Agents and Chemotherapy Vol. 50, No. 7 ( 2006-07), p. 2525-2529
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 50, No. 7 ( 2006-07), p. 2525-2529
    Abstract: The potencies of several alkoxyalkyl esters of acyclic nucleoside phosphonates against vaccinia virus and cowpox virus were evaluated in cell monolayers and three-dimensional epithelial raft cultures. Prodrugs were at least 20-fold more active than their parent compounds. Octadecycloxyethyl-( S )-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine emerged as the most potent derivative.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01489-05
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2006
    detail.hit.zdb_id: 1496156-8
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  • 5
    Online Resource
    Online Resource
    Activities of Several Classes of Acyclic Nucleoside Phosphonates against Camelpox Virus Replication in Different Cell Culture Models
    American Society for Microbiology ; 2007
    In:  Antimicrobial Agents and Chemotherapy Vol. 51, No. 12 ( 2007-12), p. 4410-4419
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 51, No. 12 ( 2007-12), p. 4410-4419
    Abstract: Camelpox virus (CMLV) is the closest known virus to variola virus. Here we report on the anti-CMLV activities of several acyclic nucleoside phosphonates (ANPs) related to cidofovir [( S )-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine (HPMPC; Vistide)] against two CMLV strains, CML1 and CML14. Cytopathic effect (CPE) reduction assays performed with human embryonic lung fibroblast monolayers revealed the selectivities of the first two classes of ANPs (cHPMPA, HPMPDAP, and HPMPO-DAPy) and of the hexadecyloxyethyl ester of 1-{[(5 S )-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine (HDE-cHPMP-5-azaC), belonging to the newly synthesized ANPs, which are HPMP derivatives containing a 5-azacytosine moiety. The inhibitory activities of ANPs against both strains were also confirmed with primary human keratinocyte (PHK) monolayers, despite the higher toxicity of those molecules on growing PHKs. Virus yield assays confirmed the anti-CML1 and anti-CML14 efficacies of the compounds selected for the highest potencies in CPE reduction experiments. Ex vivo studies were performed with a 3-dimensional model of human skin, i.e., organotypic epithelial raft cultures of PHKs. It was ascertained by histological evaluation, as well as by virus yield assays, that CMLV replicated in the human skin equivalent. HPMPC and the newly synthesized ANPs proved to be effective at protecting the epithelial cells against CMLV-induced CPE. Moreover, in contrast to the toxicity on PHK monolayers, signs of toxicity in the differentiated epithelium were seen only at high ANP concentrations. Our results demonstrate that compounds belonging to the newly synthesized ANPs, in addition to cidofovir, represent promising candidates for the treatment of poxvirus infections.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00838-07
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2007
    detail.hit.zdb_id: 1496156-8
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  • 6
    Online Resource
    Online Resource
    Antiherpesvirus Activities of Two Novel 4′-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases
    American Society for Microbiology ; 2014
    In:  Antimicrobial Agents and Chemotherapy Vol. 58, No. 8 ( 2014-08), p. 4328-4340
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 8 ( 2014-08), p. 4328-4340
    Abstract: The emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivity in vitro . While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.02825-14
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2014
    detail.hit.zdb_id: 1496156-8
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    SSG: 15,3
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  • 7
    Online Resource
    Online Resource
    KAY-2-41, a Novel Nucleoside Analogue Inhibitor of Orthopoxviruses In Vitro and In Vivo
    American Society for Microbiology ; 2014
    In:  Antimicrobial Agents and Chemotherapy Vol. 58, No. 1 ( 2014-01), p. 27-37
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 1 ( 2014-01), p. 27-37
    Abstract: The availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. In the search for novel antiviral agents, a 1′-methyl-substituted 4′-thiothymidine nucleoside, designated KAY-2-41, emerged as an efficient inhibitor of poxviruses. In vitro , KAY-2-41 was active in the micromolar range against orthopoxviruses (OPVs) and against the parapoxvirus orf. The compound preserved its antiviral potency against OPVs resistant to the reference molecule cidofovir. KAY-2-41 had no noticeable toxicity on confluent monolayers, but a cytostatic effect was seen on growing cells. Genotyping of vaccinia virus (VACV), cowpox virus, and camelpox virus selected for resistance to KAY-2-41 revealed a nucleotide deletion(s) close to the ATP binding site or a nucleotide substitution close to the substrate binding site in the viral thymidine kinase (TK; J2R ) gene. These mutations resulted in low levels of resistance to KAY-2-41 ranging from 2.7- to 6.0-fold and cross-resistance to 5-bromo-2′-deoxyuridine (5-BrdU) but not to cidofovir. The antiviral effect of KAY-2-41 relied, at least in part, on activation (phosphorylation) by the viral TK, as shown through enzymatic assays. The compound protected animals from disease and mortality after a lethal challenge with VACV, reduced viral loads in the serum, and abolished virus replication in tissues. In conclusion, KAY-2-41 is a promising nucleoside analogue for the treatment of poxvirus-induced diseases. Our findings warrant the evaluation of additional 1′-carbon-substituted 4′-thiothymidine derivatives as broad-spectrum antiviral agents, since this molecule also showed antiviral potency against herpes simplex virus 1 in earlier studies.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01601-13
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2014
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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