Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cefotiam (CTM) is a new synthetic cephem antibiotic developed in Japan. The results of the fundamental and clinical studies are as follows. 1. CTM showed antibacterial activity, in terms of MIC, as strong as those of cephalothin (CET) and cefazolin (CEZ) for Gram-positive cocci, and several times superior to for Gram-negative bacilli. 2. CTM serum levels approximately reached the peaks on completion of 60 minutes intravenous drip infusion of 1 g of this preparation dissolved in 5% glucose solution of 250 ml; the mean value was 65.00 micrograms/ml. Then the levels dropped rather quickly up to 180 minutes after the start of drip infusion. After that, the levels dropped gradually up to 360 minutes. 3. As for the passage of CTM in the oral tissues, satisfactory passage was observed in both maxillomandibular marrow and gingiva, which adequately exceeded MICs of the clinically isolated strains of oral infections. 4. This preparation was administered 1 g of 2 g daily by intravenous drip infusion in 18 cases of moderate or more serious infections in the field of oral surgery; the clinical efficacy rate obtained was 94.4%. 5. No manifestations of side effect were observed clinically. As for laboratory findings, 1 case of large increases in GOT and GTP (a hepatitis B antigen positive patient) and 2 cases of slight increase in GTP were observed. On the basis of these results of the fundamental and clinical studies, it was concluded that CTM is an excellent antibiotic for the treatment of oral infections.
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PMID:[Fundamental and clinical studies of cefotiam in the field of oral surgery]. 629 40

The novel nucleoside oxetanocin G, 9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanosyl)guanine (OXT-G), that is a derivative of oxetanocin A, was studied in relation to its action on the synthesis of hepatitis B virus (HBV) DNA and cellular DNA in an HBV-producing cell line, HB611 (T. Tsurimoto, A. Fujiyama, and K. Matsubara, Proc. Natl. Acad. Sci. USA 84:444-448, 1987). The median effective concentration of OXT-G against HBV replication was 1.5 microM, and the median cytotoxic concentration was more than 1,000 microM. At the same concentration, OXT-G did not inhibit cellular DNA synthesis or viral RNA synthesis. Chemically synthesized OXT-GTP inhibited the HBV endogenous DNA polymerase reaction and was incorporated into HBV DNA strands at a low efficiency compared with the incorporation of dGTP. A synthetic primer-template study revealed that OXT-GTP was incorporated into DNA strands at a low efficiency and that further extension of the DNA strand by using the 2' position of the incorporated OXT-G could take place.
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PMID:Effect of oxetanocin G, a novel nucleoside analog, on DNA synthesis by hepatitis B virus virions. 751 17

Intensive multidrug chemotherapy with concomitant IFN was performed in three hepatitis B virus (HBV) carriers with malignant lymphomas. All of the patients were HBsAg+, HBsAb-, HBcAb+, HBeAg- and HBeAb+ (mutant strain+). HBV-DNA polymerase (DNA-P) was normal at the beginning of chemotherapy, and complete response was achieved with CO-BLAM chemotherapy (without PDN) in all cases. In case 1, a slight elevation of DNA-P and normal GOT and GPT was observed after IFN-alpha was started during the third course. IFN-alpha was administered twice a week. In case 2, elevation of DNA-P and normal GOT and GTP were noted at the end of the 5th course, then daily IFN-alpha was started. In case 3, daily IFN-alpha was started during the 3rd course because of elevation of DNA-P. It was possible to prevent severe liver damage by administering IFN immediately after the elevation of DNA-P, since DNA-P elevation is noted before GOT and GPT elevation. The detection of the HBV mutant strain could be helpful in the treatment of HBsAg+ and HBeAb+ patients. In all of three patients, DNA-P, serum GOT and GPT normalized quickly after the administration of IFN-alpha. Severe hepatitis did not develop.
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PMID:[Chemotherapy with concomitant IFN treatment in three HBV carriers (mutant strain) with malignant lymphoma]. 756 13

The (-) enantiomers of 2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and 2',3'-dideoxy-3'-thiacytidine [(-)-BCH-189] were recently shown to inhibit selectively human immunodeficiency viruses (HIV) and hepatitis B virus in vitro. In the current study, the potential for HIV type 1 (HIV-1) resistance to these compounds was evaluated by serial passage of the virus in human peripheral blood mononuclear cells and MT-2 cells in the presence of increasing drug concentrations. Highly drug-resistant HIV-1 variants dominated the replicating virus population after two or more cycles of infection. The resistant variants were cross-resistant to (-)-FTC, (-)-BCH-189, and their (+) congeners but remained susceptible to 2',3'-dideoxycytidine, 3'-azido-3'-deoxythymidine, 3'-fluoro-3'-deoxythymidine, 2',3'-dideoxyinosine, phosphonoformate, the TIBO compound R82150, and the bis(heteroaryl)piperazine derivative U-87201E. Reverse transcriptase derived from drug-resistant viral particles was 15- to 50-fold less susceptible to the 5'-triphosphates of FTC and BCH-189 compared with enzyme from parental drug-susceptible virus. DNA sequence analysis of the reverse transcriptase gene amplified from resistant viruses consistently identified mutations at codon 184 from Met (ATG) to Val (GTG or GTA) or Ile (ATA). Sequence analysis of amplified reverse transcriptase from a patient who had received (-)-BCH-189 therapy for 4 months demonstrated a mixture of the Met-184-to-Val (GTG) mutation and the parental genotype, indicating that the Met-184 mutation can occur in vivo.
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PMID:Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. 768 16

Hepatitis B virus produces a small (154-amino acid) transcriptional transactivating protein, HBx, which is required for viral infection and has been implicated in virus-mediated liver oncogenesis. However, the molecular mechanism for HBx activity and its possible influence on cell proliferation have remained obscure. A number of studies suggest that HBx may stimulate transcription by indirectly activating transcription factors, possibly by influencing cell signaling pathways. We now present biochemical evidence that HBx activates Ras and rapidly induces a cytoplasmic signaling cascade linking Ras, Raf, and mitogen-activated protein kinase (MAP kinase), leading to transcriptional transactivation. HBx strongly elevates levels of GTP-bound Ras, activated and phosphorylated Raf, and tyrosine-phosphorylated and activated MAP kinase. Transactivation of transcription factor AP-1 by HBx is blocked by inhibition of Ras or Raf activities but not by inhibition of Ca(2+)- and diacylglycerol-dependent protein kinase C. HBx was also found to stimulate DNA synthesis in serum-starved cells. The hepatitis B virus HBx protein therefore stimulates Ras-GTP complex formation and promotes downstream signaling through Raf and MAP kinases, and may influence cell proliferation.
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PMID:Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. 793 54

The hepatitis B virus X-protein (HBx) has been expressed in Escherichia coli both as an unfused protein and with an N-terminal hexaHis-containing fusion sequence. Both forms of HBx, after purification, displayed a potent AMP kinase activity, in which HBx phosphorylates AMP to ADP, using ATP as the exclusive phosphate donor. We also found that HBx has previously unreported GTPase and GTP-ADP nucleoside diphosphate kinase activities.
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PMID:The hepatitis B virus X protein is a potent AMP kinase. 862 19

The HBx protein of hepatitis B virus (HBV) is a small transcriptional transactivator that is essential for infection by the mammalian hepadnaviruses and is thought to be a cofactor in HBV-mediated liver cancer. HBx stimulates signal transduction pathways by acting in the cytoplasm, which accounts for many but not all of its transcriptional activities. Studies have shown that HBx protein activates Ras and downstream Ras signaling pathways including Raf, mitogen-activated protein (MAP) kinase kinase kinase (MEK), and MAP kinases. In this study, we investigated the mechanism of activation of Ras by HBx because it has been found to be central to the ability of HBx protein to stimulate transcription and to release growth arrest in quiescent cells. In contrast to the transient but strong stimulation of Ras typical of autocrine factors, activation of Ras by HBx protein was found to be constitutive but moderate. HBx induced the association of Ras upstream activating proteins Shc, Grb2, and Sos and stimulated GTP loading onto Ras, but without directly participating in complex formation. Instead, HBx is shown to stimulate Ras-activating proteins by functioning as an intracellular cytoplasmic activator of the Src family of tyrosine kinases, which can signal to Ras. HBx protein stimulated c-Src and Fyn kinases for a prolonged time. Activation of Src is shown to be indispensable for a number of HBx activities, including activation of Ras and the Ras-Raf-MAP kinase pathway and stimulation of transcription mediated by transcription factor AP-1. Importantly, HBx protein expressed in cultured cells during HBV replication is shown to activate the Ras signaling pathway. Mechanisms by which HBx protein might activate Src kinases are discussed.
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PMID:Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras. 934 5

Very rapid amplification of DNA by PCR in small volumes can be continuously monitored by the detection of the binding of probes with a rapid cycler with built-in fluorometric detection. Primers were designed to amplify approximately 100 bp of the polymerase gene of hepatitis B virus (HBV) spanning codon 550, where mutations associated with resistance to lamivudine invariably occur. Four hybridization probes were synthesized: one was 3' labelled with fluorescein and hybridized upstream of codon 550. The others were 5' labelled with Cy5 and 3' labelled with biotin and spanned codon 550. The Cy5-labelled oligonucleotides contained either wild-type (ATG) or mutant (GTG or ATT) sequences. A Cy5-labelled probe and either the fluorescein-labelled probe or Sybr Green 1 (a compound that fluoresces when bound to double-stranded DNA) were included in each PCR. After completion of the amplification by using a LightCycler (Idaho Technology), the temperature at which the Cy5 probe melted from the product was determined in a melt program that took ca. 3 min. Pre- and posttreatment samples from eight patients (five chronic and three transplant) who failed lamivudine treatment were amplified, and the presence of mutations in codon 550 was determined by ABI sequencing and by using the LightCycler; in some cases PCR products were also cloned, and multiple clones were sequenced. Concordant results were obtained in all cases. We found the LightCycler to be better at resolving the sequences of genomic mixtures; for example, two samples showed a sequence at codon 550 of (A/G)T(G/T), which was found by fluorimetry to be mixtures of GTG and ATT but no ATG, and this finding was confirmed by the sequencing of clones. However, this approach was not more sensitive than population sequencing for the detection of the presence of mixtures. Overall, this pilot study has demonstrated an approach that could be an extremely rapid and economical method for the detection of lamivudine resistance-associated mutations in HBV.
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PMID:Use of real-time PCR and fluorimetry to detect lamivudine resistance-associated mutations in hepatitis B virus. 1039 Feb 10

Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is currently used as an immunosuppressive agent in kidney transplant recipients. After oral administration, MMF is hydrolysed to MPA, the active compound, which is a potent inhibitor of inosine monophosphate dehydrogenase (IMP-DH). Inhibition of this enzyme results in a depletion of the intracellular GTP and dGTP pools. MPA has been shown to inhibit the replication of a number of viruses, including arena viruses (Junin and Tacaribe), yellow fever virus, reovirus-1, parainfluenza-3 virus, Coxsackie B4 virus, Epstein-Barr virus and human immunodeficiency virus. To examine whether MPA also has an inhibitory effect on HBV replication, experiments were performed using cultures of primary human hepatocytes and HBV-transfected, HepG2 2.2.15 cells. After in vitro infection with HBV in human hepatocytes, HBV covalently-closed-circular (ccc) DNA and HBV mRNAs were detectable in the cells during the 10 days following infection. HBV DNA and hepatitis B surface antigen (HBsAg) were also secreted into the culture medium. In the presence of 10 microg ml-1 MPA (the therapeutic serum level of MPA as an immunosuppressive agent) in culture medium, HBV ccc DNA and HBV mRNAs became undetectable 5 days after treatment was started. The secretion of HBV DNA and HBsAg into the medium was also markedly reduced. No cytotoxic effect of the drug was noted during the experiments. The effect of MPA on HBV replication was abolished by the presence of guanosine (50 microg ml-1). In HepG2 2.2.15 cells (which contain an integrated tandem dimer of the HBV genome), MPA treatment had no significant inhibitory effect on the secretion of HBV DNA and HBsAg into the culture medium. HBV ccc DNA and HBV mRNAs in HepG2 2.2.15 cells were also not affected. The observed effect of MPA on HBV replication in primary human hepatocyte cultures may involve only episomal replication and may have clinical implications, especially before integration of HBV DNA into the host genome.
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PMID:Mycophenolic acid, an immunosuppressive agent, inhibits HBV replication in vitro. 1060 35

The enzyme IMP dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, namely, the conversion of IMP to XMP. The major event occurring in cells exposed to competitive IMPDH inhibitors such as ribavirin or uncompetitive inhibitors such as mycophenolic acid (MPA) is a depletion of the intracellular GTP and dGTP pools. Ribavirin is approved as an inhaled antiviral agent for treatment of respiratory syncytial virus (RSV) infection and orally, in combination with alpha interferon (IFN-alpha), for the treatment of chronic hepatitis C virus (HCV) infection. VX-497 is a potent, reversible uncompetitive IMPDH inhibitor which is structurally unrelated to other known IMPDH inhibitors. Studies were performed to compare VX-497 and ribavirin in terms of their cytotoxicities and their efficacies against a variety of viruses. They included DNA viruses (hepatitis B virus [HBV], human cytomegalovirus [HCMV], and herpes simplex virus type 1 [HSV-1]) and RNA viruses (respiratory syncytial virus [RSV], parainfluenza-3 virus, bovine viral diarrhea virus, Venezuelan equine encephalomyelitis virus [VEEV], dengue virus, yellow fever virus, coxsackie B3 virus, encephalomyocarditis virus [EMCV], and influenza A virus). VX-497 was 17- to 186-fold more potent than ribavirin against HBV, HCMV, RSV, HSV-1, parainfluenza-3 virus, EMCV, and VEEV infections in cultured cells. The therapeutic index of VX-497 was significantly better than that of ribavirin for HBV and HCMV (14- and 39-fold, respectively). Finally, the antiviral effect of VX-497 in combination with IFN-alpha was compared to that of ribavirin with IFN-alpha in the EMCV replication system. Both VX-497 and ribavirin demonstrated additivity when coapplied with IFN-alpha, with VX-497 again being the more potent in this combination. These data are supportive of the hypothesis that VX-497, like ribavirin, is a broad-spectrum antiviral agent.
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PMID:Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. 1072 82


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