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

The synthesis and in vitro anti-hepatitis B virus (HBV) activity of two mononucleoside phosphotriester derivatives of acyclovir incorporating S-acyl-2-thioethyl (SATE) groups are reported. In contrast to the parent nucleoside, the described phosphotriesters emerged as potent and selective inhibitors of HBV replication in HepG2.2.15 cells. This result can be attributed to the unique cellular metabolism of the SATE pronucleotides giving rise to the delivery to acyclovir 5'-monophosphate inside the infected cells. Moreover, the in vitro anti-HBV activities of one of these bis(SATE)phosphotriesters and of (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC) were compared alone and in combination. Analysis of the combination data indicates that 3TC and the studied SATE pronucleotide of acyclovir exhibited strong synergistic interactions. The present study provides an example where the use of a pronucleotide approach extends the antiviral spectrum of a nucleoside analogue. Given the potency of SATE pronucleotides of acyclovir against HBV in HepG2.2.15 cells, further studies including animal experiments seem warranted to evaluate the potential of these compounds as anti-HBV agents.
 ...
PMID:The S-acyl-2-thioethyl pronucleotide approach applied to acyclovir: part I. Synthesis and in vitro anti-hepatitis B virus activity of bis(S-acyl-2-thioethyl)phosphotriester derivatives of acyclovir. 1002 51

We report a case of simultaneous infection with hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) in a 26-year-old Japanese homosexual man. He was admitted to our hospital for acute hepatitis caused by HBV. At that time, HIV-1antibody (Ab) was not detected in his serum. After 6 months, he was readmitted to our hospital for further examination of his liver because of confined liver enzyme abnormalities. Anti-HIV- Ab was detected in his serum by both enzyme immunosorbent assay (EIA) and particle agglutination (PA). His serum HIV-1 RNA level was 50 x 10(4) copies/ml and serum levels of HBV DNA polymerase (DNA-P) and HBV DNA were 6535cpm and 3 plus (>1000 copies/ml). His clinical course and laboratory data suggested progression from acute to chronic hepatitis related to coinfection with HIV-1. The diagnosis was chronic active hepatitis caused by HBV as an opportunistic infection due to coinfection with HIV-1. We began highly active antiretroviral therapy (HAART) because interferon (IFN) therapy was ineffective. HAART was started at an initial dosage of 600 mg zidovudine (AZT), 300 mg lamivudine (3TC), and 2400 mg indinavir (IDV) daily. After 4 weeks, the serum level of HBV DNA-polymerase (p) had decreased markedly to 37cpm and that of HIV-1 RNA had decreased to below the sensitivity threshold, indicating considerable suppression of the replication of these viruses by the treatment. But HBV DNA remained at low levels. Although the incidence of HBV infection in patients with HIV-1 infection has been reported to be high in the United States and Europe, simultaneous HBV and HIV-1 infection leading to persistent HBV infection is rare.
 ...
PMID:Highly active antiretroviral therapy used to treat concurrent hepatitis B and human immunodeficiency virus infections. 1021 32

Lamivudine is a new antiviral agent effective against hepatitis B viral (HBV) infections but can result in virus-drug resistance associated with mutations in the conserved 'YM552DD' motif of the HBV DNA polymerase. Due to their overlapping coding regions in the HBV genome, mutations in the DNA polymerase may result in substitutions in the hepatitis B surface antigen (HBsAg), albeit outside the antigenic 'a' epitope. Here we report the identification of a novel type of lamivudine-related mutations located in both the polymerase (YM552DD-->Y1552DD) and the 'a' epitope of HBsAg (Gly130-->Asp130). The same virus carried a HBsAg Gly145-->Arg145 mutation prior to therapy. Both the wild type HBV and lamivudine-related mutants with the Gly145-->Arg145 HBsAg mutation were suppressed following ganciclovir treatment, indicating a beneficial additive effect of both drugs against different forms of HBV mutants.
 ...
PMID:Hepatitis B virus variants with lamivudine-related mutations in the DNA polymerase and the 'a' epitope of the surface antigen are sensitive to ganciclovir. 1032 44

A large percentage of human immunodeficiency virus (HIV) patients have serological evidence of a past or present hepatitis B virus infection (HBV). Long-term survival is increasing for HIV patients because of highly active antiretroviral therapy. Therefore, the chronic hepatitis B infection may become an important determinant of disease outcome in these co-infected patients. We describe two HIV/HBV co-infected patients who were treated with extended antiviral therapy, initially indicated for the HIV infection. Lamivudine, a suppressor of viral replication in both infections, was one of these antiviral drugs. One patient showed a severe rebound of the HBV after withdrawal of lamivudine, the other patient developed a mutant hepatitis B virus after 18 months of treatment. This mutation was exclusively induced by lamivudine. These patients show that, with improved HIV-related survival, the HBV infection should be monitored carefully, thereby enabling the physician to interfere with therapy when necessary.
 ...
PMID:Antiviral treatment for human immunodeficiency virus patients co-infected with hepatitis B virus: combined effect for both infections, an obtainable goal? 1033 44

L-(-)2',3'-Dideoxythiacytidine (L(-)SddC, Lamivudine) resistant hepatitis B virus (HBV) develops in patients after prolonged treatment. Point mutations detected in the viral genome from these patients have been shown to be responsible for L(-)SddC resistance. Therefore, new drugs active against L(-)SddC resistant HBV are needed. Using a transient transfection system, we studied the sensitivity of L(-)SddC resistant HBV to other anti-HBV nucleoside analogues. It was found that the L526M mutation alone caused greater resistance to penciclovir (PCV) than did the V553I mutation alone. Both mutations also caused the virus to be less sensitive to L(-)SddC and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), although the degree of resistance was much less than that to PCV. The A546V mutation had no impact on the sensitivity to L(-)SddC, L-FMAU, and PCV. When these single mutations were coupled with the M550V/I mutation, all the double mutants were resistant to those drugs. Although 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine (L(-)Fd4C) was also less active, the IC50 of L(-)Fd4C against the L(-)SddC resistant mutant was at least fifty times lower than that against cell growth in culture. DNA polymerase associated with L(-)SddC resistant virions was also found to be less sensitive than that with wild-type HBV to those L-nucleoside triphosphates. All the L(-)SddC resistant mutants were still sensitive to 9-(2-phosphonylmethoxyethyl)-adenine (PMEA). These results suggest that different mutations in the HBV genome have a different impact on its sensitivity to those compounds, and L(-)SddC resistant HBV may also be resistant to PCV, L-FMAU, and L(-)Fd4C. A nucleoside analogue less toxic than PMEA could be developed against L(-)SddC resistant HBV.
 ...
PMID:Sensitivity of L-(-)2,3-dideoxythiacytidine resistant hepatitis B virus to other antiviral nucleoside analogues. 1035 55

The emergence of resistant hepatitis B virus (HBV), with mutations in the YMDD motif of the polymerase gene after treatment with lamivudine, is becoming an important clinical problem. In this study, susceptibility of wild-type and lamivudine-resistant HBV M552I, M552V, and L528M/M552V mutants to other reverse transcriptase inhibitors was investigated by transient transfection of full-length HBV DNA into human hepatoma cells. HBV DNA replication was monitored by Southern blot hybridization, which showed the presence of a single-stranded band (representative of the HBV replicative intermediates) in the drug-free, wild-type HBV-transfected cells. This band was diminished in the samples of wild-type HBV DNA treated with either lamivudine, adefovir, or lobucavir. The band intensities from the lamivudine-resistant mutants were not decreased by treatment with lamivudine, but were decreased by the treatments with adefovir or lobucavir. In contrast, penciclovir and nevirapine did not diminish the intensity of the single-stranded band of wild-type HBV or the lamivudine-resistant mutants. These results demonstrate that lamivudine-resistant HBV is susceptible to adefovir and lobucavir. Lamivudine-resistant HBV should be treated with adefovir or lobucavir, and combination therapy with lamivudine and adefovir/lobucavir may prevent the emergence of lamivudine-resistant HBV.
 ...
PMID:Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors. 1037 69

The clinical features and treatment of chronic hepatitis C in Chinese patients are the same as in Caucasian patients except that 27% of Chinese chronic hepatitis C patients have hepatitis C virus (HCV) genotype 6a. In contrast, Chinese patients with chronic hepatitis B (CHB) differ from Caucasian patients because the Chinese patients are immunologically tolerant to hepatitis B virus (HBV), having acquired hepatitis B infection perinatally or in early childhood. In the treatment of CHB, the short-term aims of loss of hepatitis B virus early antigen (HBeAg) and HBV-DNA need to be reassessed. In 1296 Chinese CHB patients, 67.7% of those who developed complications of cirrhosis or hepatocellular carcinoma, were HBeAg-antibody positive. Longer follow up of patients is, therefore, required to assess the time efficacy of a treatment regimen. After long-term follow up (median 90 months) of 206 Chinese CHB patients treated with interferon alpha (IFN alpha) compared with 203 untreated subjects, IFN alpha conferred no benefit in cumulative HBeAg seroconversion or in HBV-DNA negativity as determined by polymerase chain reaction assays or in decreasing long-term complications of cirrhosis and hepatocellular carcinoma. Lamivudine is a novel nucleoside analogue. In a recent 1 year study in 358 Chinese CHB patients, lamivudine treatment was associated with substantial histological improvement (including a reduction in fibrosis), with HBV-DNA suppression and normalization of alanine aminotransferase levels. However, lamivudine may have to be given on a long-term basis, as withdrawal of lamivudine results in rebound of HBV-DNA to pretreatment levels. The long-term effects of lamivudine are currently being assessed.
 ...
PMID:Antiviral therapy for hepatitis B and C in Asians. 1038 33

A recently developed transgenic mouse strain which expresses high levels of hepatitis B virus (HBV) was studied as a model for evaluation of potential chemotherapeutic agents. Lamivudine ([-]2'-deoxy-3'-thiacytidine), known to reduce hepatitis B viremia in human patients, and zidovudine (3'-azido-3'-deoxythymidine), previously shown to be ineffective for HBV infections in man, were used in parallel in this transgenic animal model. Orally administered lamivudine at dosages of 100, 50, and 25 mg/kg per day given once a day for 21 days significantly decreased serum and liver HBV DNA titers in a dose-responsive manner. Zidovudine (approximately 22 mg/kg per day) administered in the drinking water for 21 days was not effective in reducing these HBV parameters as compared to transgenic placebo-treated controls. The serum HBV DNA titers rebounded to high levels 1 week after cessation of lamivudine treatment. Male and female mice responded in a similar manner to these therapies. The results using this transgenic mouse model were similar to what would be predicted from treatment of HBV-infected human patients with lamivudine and zidovudine, and indicate these mice may be useful as a small animal chemotherapeutic model for study of potential HBV inhibitors.
 ...
PMID:Utilization of transgenic mice replicating high levels of hepatitis B virus for antiviral evaluation of lamivudine. 1038 53

Several new nucleoside analogues have been developed which can inhibit hepatitis B replication by at least two logs. Lamivudine is the most widely studied of these new agents. Extensive phase II and III studies in patients with chronic hepatitis B have been completed. The sustained HBeAg seroconversion rate in patients who have received 100 mg lamivudine increases from 17% after a year of treatment to 27% after 2 years of treatment. Histological improvement has been noted in 38%-52% of lamivudine-treated patients, exceeding the improvement seen in placebo recipients. Similar histological improvement has been noted in anti-HBe-positive, DNA- positive patients. Lamivudine can prevent recurrence of hepatitis B after liver transplantation. It is likely that in the absence of immune clearance to accelerate elimination of infected hepatocytes, inhibitors of virus replication such as lamivudine will need to be administered for a long period to reduce the burden of infected hepatocytes in the liver, and to prevent relapse. The drug is generally well tolerated with few direct adverse events. Genotypic mutations have been observed in 23% (range 13-32%). In a study in Asian patients treated for two years the incidence of these mutants increased to 38% (as detected by PCR). Loss of susceptibility to lamivudine has been found to be due to reverse transcriptase amino acid substitutions. Lamivudine is likely to be reserved for patients with replicative hepatitis B infection with active chronic hepatitis, and/or active cirrhosis. Copyright 1998 John Wiley & Sons, Ltd.
 ...
PMID:Lamivudine treatment of chronic hepatitis B. 1039 3

Chronic delta hepatitis is a severe form of chronic liver disease caused by hepatitis delta virus (HDV) infection superimposed on chronic hepatitis B or the hepatitis B surface antigen (HBsAg) carrier state. Therapy of delta hepatitis is currently unsatisfactory. We have evaluated lamivudine (3-thiacytidine), an oral nucleoside analogue with marked effects against hepatitis B, as therapy in 5 patients with chronic hepatitis D. Five men, ages 38 to 65 years, were treated. All had HBsAg, antibody to HDV, and HDV RNA in serum, as well as persistent elevations in alanine aminotransferase (ALT) levels and liver histology showing severe chronic hepatitis with fibrosis or cirrhosis. Lamivudine was given in a dose of 100 mg orally daily for 12 months. Patients were monitored carefully and tested for HBsAg, HBV-DNA and HDV-RNA levels serially during the year of treatment and for 6 months thereafter. Liver biopsies were performed before therapy and repeated after 1 year. Serum levels of HBV DNA fell rapidly in all 5 patients, becoming undetectable even by polymerase chain reaction (PCR) in 4. However, all 5 patients remained HBsAg- and HDV-RNA-positive, and serum ALT levels and liver histology did not improve. All patients tolerated therapy well. When lamivudine was stopped, HBV-DNA levels returned to pretreatment values without a change in disease activity. Lamivudine is a potent inhibitor of HBV-DNA replication, but does not improve disease activity or lower HDV-RNA levels in patients with chronic delta hepatitis.
 ...
PMID:Lamivudine for chronic delta hepatitis. 1042 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>