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)

The 2'-fluorinated arabinosyl-pyrimidine nucleosides, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), are new antiviral compounds with in vitro inhibitory activity against the DNA polymerase of hepadnaviruses. Those compounds also induced permanent inhibition of viral replication in woodchucks chronically infected by woodchuck hepatitis virus. The effects of these antiviral compounds were assessed in ducks chronically infected by duck hepatitis B virus (DHBV). Following intraperitoneal administration for 5 days, FMAU (2 mg/kg/day) and FIAC (10 mg/kg/day) induced a transient decrease in DHBV replication, as shown by the decrease in both the serum and liver DHBV DNA level. After stopping therapy, DHBV replication rebounded immediately to the pretreatment level. The supercoiled form of liver viral DNA was found to be less affected by the therapy. By contrast, no obvious antiviral effect was observed with vidarabine monophosphate (ara-AMP) (80 mg/kg/day) therapy. No sign of toxicity was observed during the course of the treatment. These preliminary results confirmed in the DHBV model the higher efficacy of FIAC and FMAU as compared to ara-AMP. Pharmacokinetic studies are needed to explain the differences observed in viral replication in these 2 models of HBV infection.
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PMID:Effects of 2'-fluorinated arabinosyl-pyrimidine nucleosides on duck hepatitis B virus DNA level in serum and liver of chronically infected ducks. 162 11

Duck cultured hepatocytes from Pekin ducks naturally infected by duck hepatitis B virus can remain functional twice longer if a coculture system with rat liver epithelial cells is used instead of ordinary primary culture. The use of a selective medium in which ornithine and lactate replaced arginine and glucose, respectively, allowed viral replication initiated in vivo to be maintained in the coculture for 2 months. Several antiviral compounds including the pyrophosphate analog (phosphonoformic acid) or nucleoside analogs (9 beta-arabinofuranosyl AMP, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine, 1,2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-ethyluracil and 1,2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl thymine) were studied in both culture systems for their ability to inhibit duck hepatitis B virus replication. Hepatocytes were treated for 7 days with 1,2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-ethyluracil (10 microM) and 1,2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl thymine (0.5 microM) or for 14 days with 9 beta-arabinofuranosyl AMP (90 microM), phosphonoformic acid (100 microM) and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (6 microM). The effects of the drugs on viral replication were monitored by testing for duck hepatitis B virus DNA in the culture supernatant and in the cells by molecular hybridization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prolonged duck hepatitis B virus replication in duck hepatocytes cocultivated with rat epithelial cells: a useful system for antiviral testing. 254 88

A conjugate of the antiviral agent adenine arabinoside monophosphate (ara-AMP) with a low molecular mass lactosaminated poly-L-lysine, administered to mice by i.m. route, selectively delivers the drug to the liver. In mice the conjugate is devoid of acute toxicity even at high dose (1.3 mg/g) and injected i.m. for 20 days does not induce antibodies. Moreover it is highly soluble in water; this means that a pharmacologically active dose may be administered in a small volume compatible with the i.m. route. Compared to the similar ara-AMP complex with lactosaminated albumin which must be injected intravenously, the present conjugate might assure a better compliance of patients with hepatitis B virus infection for a long lasting, liver targeted antiviral treatment.
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PMID:A conjugate of lactosaminated poly-L-lysine with adenine arabinoside monophosphate, administered to mice by intramuscular route, accomplishes a selective delivery of the drug to the liver. 751 Apr 78

Hepatitis B virus infection is responsible for both morbidity and mortality in kidney transplant recipients. Adenine arabinoside 5'-monophosphate (ARA-AMP), a synthetic purine nucleotide with anti-viral activity, leads to a sustained interruption of HBV replication in approximately 40% of immunocompetent patients. We report the results of a pilot study using ARA-AMP to treat HBV-related chronic active hepatitis in kidney transplant recipients. Ten patients (2 females and 8 males, mean age 44 years, mean time post-transplantation 163 months) received a 28-day course of ARA-AMP intramuscularly: 5 mg/kg twice daily for the first 5 days during hospitalization and subsequently 5 mg/kg once daily at home for the remaining 23 days. Mean follow-up was 18 months, ranging from 7 to 28 months. All patients but one had biopsy-proven chronic hepatitis, including five cases of cirrhosis. All patients had been chronic HBs Ag carriers for more than 1 year and had active replication as assessed by the presence of serum HBV DNA (mean titre, 270 pg/ml, ranging from 12 to 997 pg/ml, Genostics method). HBe Ag was present in 7 of the 10 patients. Pretreatment creatinine was normal. In four of the 10 patients, HBV DNA became undetectable respectively 1, 1, 5, and 11 months after beginning ARA-AMP. In five patients, HBV DNA decreased during ARA-AMP therapy but subsequently increased although no change was noted during the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effectiveness of adenine arabinoside 5'-monophosphate in kidney transplant recipients with chronic active hepatitis B. 752 77

This study compared the response to adenine arabinoside 5'-monophosphate (ARA AMP) in 60 patients with chronic hepatitis B according to the pretreatment serum hepatitis B virus DNA concentration. The level of hepatitis B virus replication was defined as low (30 patients) or high (30 patients) when serum hepatitis B virus DNA concentration was below or above 100 pg/ml, respectively. Patients received a 28 day course of ARA AMP and a second course of ARA AMP was given six months later to patients with persistent hepatitis B virus replication. At the end of the first course of ARA AMP, 11 of the patients (37%) with low replication and one of the patients (3%) with high replication became negative for hepatitis B virus DNA (p = 0.0012); five of the patients (17%) with low replication and none of the patients with high replication had HBe seroconversion (p = 0.06). Two of these five patients lost HBsAg. Kinetics of serum hepatitis B virus DNA during treatment showed a considerable but transient antiviral effect of ARA AMP. Three of 32 retreated patients became negative for hepatitis B virus DNA and one patient had HBe seroconversion. In conclusion, ARA AMP exerts a considerable but transient antiviral effect on hepatitis B virus. Complete and sustained inhibition of hepatitis B virus replication was only obtained in the patients with low hepatitis B virus replication.
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PMID:Adenine arabinoside 5'-monophosphate in patients with chronic hepatitis B: comparison of the efficacy in patients with high and low viral replication. 753 85

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 effect of glucagon on the establishment of hepadnavirus infection was studied in vitro with the duck hepatitis B virus (DHBV) model. The presence of the peptide hormone throughout infection or starting up to 8 h after virus uptake resulted in a dose-dependent reduction in the levels of intra- and extracellular viral gene products and of secreted virions. Treatment with forskolin or dibutyryl-cyclic AMP, two drugs that also stimulate the cyclic AMP (cAMP) signal transduction pathway, resulted in comparable inhibition, suggesting that the inhibitor effect is related to changes in the activity of protein kinase A. In persistently infected hepatocytes, only a slight, but continuous, decrease in viral replication was observed upon prolonged drug treatment. Time course analysis, including detection of DHBV covalently closed circular (ccc) DNA templates, revealed that glucagon acts late during the establishment of infection, at a time when the virus is already internalized, but before detectable ccc DNA accumulation in the nucleus. These data suggest that nuclear import (and reimport) of DHBV DNA genomes from cytosolic capsids is subject to cAMP-mediated regulation by cellular factors responding to changes in the state of the host cell.
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PMID:Glucagon treatment interferes with an early step of duck hepatitis B virus infection. 952 76

Hepatitis delta virus infection sometimes causes severe and fulminant hepatitis as a coinfection or superinfection along with the hepatitis B virus. To elucidate the underlying mechanism of injury caused by hepatitis delta virus, we examined whether two isoforms of the hepatitis delta antigen (HDAg) had any effect on five well defined intracellular signal transduction pathways: serum response factor (SRF)-, serum response element (SRE)-, nuclear factor kappaB-, activator protein 1-, and cyclic AMP response element-dependent pathways. Reporter assays revealed that large HDAg (LHDAg) activated the SRF- and SRE-dependent pathways. In contrast, small HDAg (SHDAg) did not activate any of five pathways. LHDAg enhanced the transcriptional ability of SRF without changing its DNA binding affinity in an electrophoretic mobility shift assay. In addition, LHDAg activated a rat SM22alpha promoter containing SRF binding site and a human c-fos promoter containing SRE. In conclusion, LHDAg, but not SHDAg, enhances SRF-associated transcriptions. Despite structural similarities between the two HDAgs, there are significant differences in their effects on intracellular signal transduction pathways. These results may provide clues that will aid in the clarification of functional differences between LHDAg and SHDAg and the pathogenesis of delta hepatitis.
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PMID:Large isoform of hepatitis delta antigen activates serum response factor-associated transcription. 1096 86

Numerous studies have demonstrated that the hepatitis B virus HBx protein stimulates signal transduction pathways and may bind to certain transcription factors, particularly the cyclic AMP response element binding protein, CREB. HBx has also been shown to promote early cell cycle progression, possibly by functionally replacing the TATA-binding protein-associated factor 250 (TAF(II)250), a transcriptional coactivator, and/or by stimulating cytoplasmic signal transduction pathways. To understand the basis for early cell cycle progression mediated by HBx, we characterized the molecular mechanism by which HBx promotes deregulation of the G0 and G1 cell cycle checkpoints in growth-arrested cells. We demonstrate that TAF(II)250 is absolutely required for HBx activation of the cyclin A promoter and for promotion of early cell cycle transit from G0 through G1. Thus, HBx does not functionally replace TAF(II)250 for transcriptional activity or for cell cycle progression, in contrast to a previous report. Instead, HBx is shown to activate the cyclin A promoter, induce cyclin A-cyclin-dependent kinase 2 complexes, and promote cycling of growth-arrested cells into G1 through a pathway involving activation of Src tyrosine kinases. HBx stimulation of Src kinases and cyclin gene expression was found to force growth-arrested cells to transit through G1 but to stall at the junction with S phase, which may be important for viral replication.
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PMID:Hepatitis B virus HBx protein activation of cyclin A-cyclin-dependent kinase 2 complexes and G1 transit via a Src kinase pathway. 1128 74

Bullatacin, a potential antitumor Annonaceous acetogenin (AA), is isolated from the seed of the Formosa Annona atemoya. We reported previously that bullatacin inhibits the secretion of hepatitis B surface antigen from 2.2.15 cells (human hepatoma HepG2 cells transfected with hepatitis B virus DNA plasmid). In the present study, we determined cell apoptosis by using double-dye staining with fluorescein-isothiocyanate-labeled annexin V and propidium iodide. We found that bullatacin induced apoptosis in 2.2.15 cells in a time-dependent manner; the most significant apoptotic change appeared at 16 hr. Moreover, different concentrations (10(-3) to 1.0 microM) of bullatacin induced apoptosis in a concentration-dependent manner at 16 hr. The determination of intracellular cyclic AMP (cAMP) and cyclic GMP (cGMP) levels in 2.2.15 cells after exposure to bullatacin demonstrated that bullatacin caused both to decrease in a time- and concentration-dependent manner. A time course (0.33, 1, 6, 16, 24hr) study indicated that while both cAMP and cGMP levels decreased early (at 0.33 hr), the most dramatic decline appeared at 6 hr. Meanwhile, the inhibitory effect on cAMP and cGMP levels reached a maximum at 16 hr (90.5+/-3.2 and 47.3+/-12.8%, respectively). The concentration-dependent decrease of both cAMP and cGMP induced by bullatacin was parallel with the magnitude of apoptosis induced by various concentrations (10(-3) to 1.0 microM) of bullatacin. Additionally, the bullatacin-induced apoptosis was inhibited by the addition of cAMP and cGMP elevating agents (forskolin and S-nitrosoglutathione). Our results suggest that a decrease of both cAMP and cGMP levels may play a crucial role in bullatacin-induced apoptosis in 2.2.15 cells.
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PMID:Bullatacin, a potent antitumor Annonaceous acetogenin, induces apoptosis through a reduction of intracellular cAMP and cGMP levels in human hepatoma 2.2.15 cells. 1252 25


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