Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lamivudine (3TC) is a nucleoside analogue which inhibits replication of HIV and HBV and which is used in the treatment of chronic hepatitis B-infected patients with safety and efficacy. The activity of lamivudine was evaluated by the measurement of DNA-HBV concentration in plasma using a very sensitive assay (1,000 copies/mL) (Amplicor VHB Monitor. Roche). Ten patients chronically infected with hepatitis B (group A) and 24 patients with HIV-1 co-infection (group B) were enrolled. In 9 patients of group A, HBVDNA load was undetectable a median of 3.5 months after the beginning of treatment and remained negative for 2 years with hepatitis Be antigen disappearing and normal alanine aminotransferase concentration. In the last immunodeficient patient, the virus which had been resistant to three interferon treatments, was also resistant to lamivudine. In five patients of group B, HBV DNA load remained undetectable after 18 months with HBe antigen disappearing and baseline concentration of alanine aminotransferase. In the remaining 19 patients after a transient decrease of HBV DNA concentration for one year, HBV DNA load increased again without disappearing of HBe antigen and without decrease of alanine aminotransferase concentration showing lamivudine resistant hepatitis B virus. Mutations in the YMDD motif of the DNA polymerase gene were identified in 11 patients (3 with M550V/I mutation; 7 with M550V/I and L256M mutations; 1 with M550V/I, L526M and V519L mutations). In 6 of these patients, was found a M184V mutation in the VIH polymerase. No correlation could be observed between the mutations detected in the two viruses. Using a sensitive HBV-DNA assay, efficacy of lamivudine for a long time in HBV infected patients was proved. However, the prevalence of lamivudine resistance is related to duration of treatment and it may be necessary to use a multitherapy.
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PMID:[Evaluation of a quantitative HBV-DNA PCR assay in lamivudine treated hepatitis B-infected patients]. 1236 44

The emergence of drug-resistant virus in hepatitis B virus (HBV) patients treated with lamivudine is well documented. In this study, we determined the mutations occurring in the tyrosine-methionine-aspartate-aspartate (YMDD) amino acid motif of the HBV DNA polymerase gene, as well as upstream and downstream of this region, in patients with breakthrough virus during lamivudine therapy. Thirty-one Turkish patients (20 patients HBeAg positive, 11 patients HBeAg negative and anti-HBe positive) with chronic HBV infection who completed at least 104 weeks of lamivudine treatment were investigated. All patients received lamivudine, (150 mg/day), for 104 weeks, with or without 4 months of interferon (IFN) combination. HBV-specific sequences were amplified by polymerase chain reaction (PCR) from sera of patients with breakthrough virus, and the PCR products were directly analysed by sequencing. Breakthrough virus was detected in seven of the 31 patients (22.6%) between 9 and 18 months of therapy. Of the seven patients, six were HBeAg positive at baseline, and four had a double mutation consisting of rtM204V and rtL180M, while two had an rtM204I change. In one patient, two base substitutions at rt204 (ATG --> AGT; T to G and G to T) lead to a methionine to serine change (YMDD --> YSDD). This novel DNA pol mutation was detected at month 18 of lamivudine treatment. In addition, this new variant had the rtL180M mutation and a 12 base pair deletion in the pre-S1 region between nucleotides 43-54. The YSDD mutation was still present 6 months after lamivudine discontinuation. In vitro transfection studies also confirmed that the YSDD strain is resistant to lamivudine. In conclusion, the results indicate that, in addition to a Met --> Val and Met --> Ile change in YMDD, a Met --> Ser change at rt204 (YMDD --> YSDD) associated with the rtL180M change can also emerge during lamivudine treatment, which confers lamivudine resistance in vivo and in vitro, leading to virological breakthrough and ALT increases.
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PMID:YSDD: a novel mutation in HBV DNA polymerase confers clinical resistance to lamivudine. 1282 91

After several weeks of treatment, levels of alanine aminotransferase (ALT) increase in 50% of patients treated with tacrine for Alzheimer's disease. We looked for progressive effects on DNA to explain delayed toxicity. We first studied the in vitro effects of tacrine on DNA replication and topoisomerase-mediated DNA relaxation. We then treated mice with doses of tacrine reproducing the human daily dose on a body area basis and studied the effects of tacrine administration for up to 28 days on hepatic DNA, mitochondrial function, and cell death. In vitro, tacrine impaired DNA polymerase gamma-mediated DNA replication and also poisoned topoisomerases I and II to increase the relaxation of a supercoiled plasmid. In vivo, administration of tacrine markedly decreased incorporation of [(3)H]thymidine into mitochondrial DNA (mtDNA), progressively and severely depleted mtDNA, and partly unwound supercoiled mtDNA into circular mtDNA. Incorporation of [(3)H]thymidine into nuclear DNA (nDNA) was barely decreased, and nDNA levels were unchanged. After 12 to 28 days of treatment, administration of tacrine increased p53, Bax, mitochondrial permeability transition, cytosolic cytochrome c, and caspase-3 activity and triggered hepatocyte apoptosis and/or necrosis. In conclusion, the intercalating drug tacrine poisons topoisomerases and impairs DNA synthesis. Tacrine has been shown to accumulate within mitochondria, and it particularly targets mtDNA. After several weeks of treatment, the combination of severe mtDNA depletion and a genotoxic stress enhancing p53, Bax, and permeability transition trigger hepatocyte necrosis and/or apoptosis.
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PMID:Tacrine inhibits topoisomerases and DNA synthesis to cause mitochondrial DNA depletion and apoptosis in mouse liver. 1293 98

Breakthroughs during lamivudine therapy were assessed according to hepatitis flares and mutational polymorphism of hepatitis B virus (HBV) infecting patients. Of 42 patients with chronic hepatitis B and positive for hepatitis B e antigen in serum, 13 (30%) harbored HBV mutants with lamivudine resistance after a mean duration of 29 months on lamivudine. The virological breakthrough occurred 14.5 months after the start of lamivudine treatment, and all the patients with it developed breakthrough hepatitis 3 months later. The clinical course of breakthrough hepatitis was self-limited except in one patient who had already developed cirrhosis at the baseline. One year after breakthrough hepatitis, serum ALT, albumin, prothrombin time and platelet counts were maintained well on conventional treatments without resorting to interferon. Major HBV mutants during breakthrough hepatitis were those with M552I in the YMDD motif of viral DNA polymerase/reverse transcriptase in 7 patients (54%), M552I/L528M in 4 patients (31%) and M552V/L528M in 2 patients (15%). There were no patients in whom mutations at nucleotide 529 occurred including the 2 who later developed hepatocellular carcinoma. There was no clear relationship between distinct mutational patterns and clinical courses. Further studies are needed for making out the effects of lamivudine-resistant mutants on clinical outcomes, taking into considerations genotypes of HBV.
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PMID:Subclones of drug-resistant hepatitis B virus mutants and the outcome of breakthrough hepatitis in patients treated with lamivudine. 1468 51

We report a case of fatal liver failure due to reactivation of lamivudine-resistant HBV. A 53-year-old man was followed since 1998 for HBV-related chronic hepatitis. Serum HBV-DNA was 150 MEq/mL (branched DNA signal amplification assay) and ALT levels fluctuated between 50-200 IU/L with no clinical signs of liver cirrhosis. Lamivudine (100 mg/d) was started in May 2001 and serum HBV-DNA subsequently decreased below undetectable levels. In May 2002, serum HBV-DNA had increased to 410 MEq/mL, along with ALT flare (226 IU/L). The YMDD motif in the DNA polymerase gene had been replaced by YIDD. Lamivudine was continued and ALT spontaneously decreased to the former levels. On Oct 3 the patient presenting with general fatigue, nausea and jaundice was admitted to our hospital. The laboratory data revealed HBV reactivation and liver failure (ALT: 1828 IU/L, total bilirubin: 10 mg/dL, and prothrombin INR: 3.24). For religious reasons, the patient and his family refused blood transfusion, plasma exchange and liver transplantation. The patient died 10 d after admission. The autopsy revealed remarkable liver atrophy.
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PMID:Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant. 1516 53

Adefovir dipivoxil, a nucleotide analog of adenosine monophosphate, is an antiviral agent that suppresses hepatitis B virus (HBV) replication through inhibition of DNA polymerase and by chain termination. To determine the effectiveness of adefovir, three populations of patients with chronic hepatitis B patients were studied: hepatitis B e antigen (HBeAg)-positive patients, HBeAg-negative patients, and patients with lamivudine-resistant tyrosine-methionine-asparate-aspartate (YMDD) mutants. All three groups of patients were treated for 48 weeks with adefovir 10 mg/d, and significant reduction in serum HBV DNA and normalization of serum alanine aminotransferase (ALT) were noted. Significant improvement in liver histology was noted in HBeAg-positive and in HBeAg-negative patients. Significant HBeAg loss and HBeAg seroconversion rates were noted in HBeAg-positive patients and in lamivudine-resistant patients. No major drug-related side effects were noted. Adefovir 10 mg/d orally is safe and effective for treatment of chronic hepatitis B.
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PMID:Treatment of patients with chronic hepatitis B with adefovir dipivoxil. 1519

A meeting of physicians and scientists involved in the management of chronic hepatitis B (CHB) was held to review current scientific data regarding antiviral resistance in hepatitis B virus (HBV) infection. The goals of the meeting were to describe current treatments for CHB, discuss emerging issues in HBV drug resistance and to delineate patient monitoring, including markers for resistance, during administration of antiviral therapy. The aim of this review article is to provide treating physicians with a framework for the management of CHB in the context of antiviral resistance. Definitions of primary and secondary antiviral treatment failure can be used to aid monitoring and early diagnosis of drug resistance before disease progression occurs as a consequence of viral breakthrough. Primary antiviral treatment failure is defined as failure of a drug to reduce HBV DNA levels by > or = 1 x log10 IU/ml within 3 months following initiation of therapy, and secondary antiviral treatment failure as a rebound of HBV replication of > or = 1 x log10 IU/ml from nadir in patients with an initial antiviral treatment effect (> or = 1 x log10 IU/ml decrease in serum HBV DNA). Confirmation of antiviral drug failure can be established by sequencing the HBV DNA polymerase and identifying specific genetic markers of antiviral drug resistance. In addition to virological assays, HBV resistance can be assessed from a clinical perspective including increased serum alanine aminotransferase levels and the development of systemic symptoms or signs of liver failure. Potential strategies to prevent the emergence of resistance and how to manage drug-resistant HBV once it emerges are discussed.
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PMID:Management of antiviral resistance in patients with chronic hepatitis B. 1553 5

Adefovir is classified as a nucleotide reverse transcriptase inhibitor because it acts by inhibiting hepatitis B virus DNA polymerase (reverse transcriptase) and causing DNA chain termination after its incorporation into the viral DNA. Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (alanine [ALT] or aspartate [AST]) or histologically active disease. It is useful in the treatment of patients with either hepatitis B e antigen-positive or -negative chronic hepatitis B. The recommended adefovir dipivoxil dose in the treatment of chronic hepatitis B in patients with adequate renal function is 10 mg once daily. Adefovir dipivoxil therapy can reduce viral load, improve ALT, and produce histologic improvement in patients with chronic hepatitis B. Improvements are generally seen within the first few weeks of therapy and have shown persistence up to at least 3 years with continued therapy. Therapy with adefovir dipivoxil is generally well tolerated. However, nephrotoxicity is a risk with adefovir therapy, especially in patients receiving higher doses (30-120 mg/d). Patients should have their renal function monitored closely throughout therapy and may require an adjustment in dose relative to changes in the creatinine clearance. Lactic acidosis and severe hepatomegaly with steatosis may also occur during therapy.
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PMID:Adefovir dipivoxil: focus on its use in the treatment of chronic hepatitis B. 1597 40

We report a patient whose cryoglobulinemic vasculitis recurred due to reactivation of lamivudine-resistant HBV. Our patient with hepatitis B-related cryoglobulinemic vasculitis was administered lamivudine. Her vasculitis regressed, ALT normalized, HBV-DNA became negative. Under lamivudine therapy, her cryoglobulinemic cutaneous vasculitis recurred. ALT increased significantly; it was found that tyrosine-methionine-aspartate-aspartate (YMDD) motif in the DNA polymerase gene had been replaced by YIDD. Adefovir was added to lamivudine. During follow-up, her purpura disappeared, ALT normalized, HBV-DNA became negative. Our patient is the first whose cryoglobulinemic vasculitis recurred under lamivudine, who had a HBV virologic breakthrough with YMDD mutation, and was successfully treated with adefovir.
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PMID:Successful treatment with adefovir of one patient whose cryoglobulinemic vasculitis relapsed under lamivudine therapy and who was diagnosed to have HBV virologic breakthrough with YMDD mutations. 1713 20

To evaluate the effects of aging on DNA damage, spontaneous and chemical-induced DNA damage and its repair were examined using comet assays at pH 9, 12.1 and 13, and an 8-OH-dG assay in the liver and kidney of young (9-week-old) and aged (20-month-old) rats. Additionally, blood chemistry was examined to investigate any correlation between vital functions and age-dependent DNA damage. DNA migration at pH 13 and 8-OH-dG levels increased in the liver and/or kidney of aged rats, but DNA migration did not increase at pH 9 or 12.1; that is, alkali-labile sites and 8-OH-dG were concomitantly accumulated in aged rats. These results suggest that 8-OH-dG production caused by reactive oxygen species exceeded glycosylation and that the glycosylation activity is far more than the AP endonucleation in aged rats. Methyl methanesulfonate (MMS, 80 mg/kg, i.p.) increased DNA migration at pH 12.1 and 13 in the liver and kidney at 3 and 24 hr after treatment in young and aged rats. The DNA damage in aged rats was less and decreased more slowly compared with young rats. The pictures of MMS-induced DNA migrations at pH 12.1 and 13 were very similar to each other. These results suggest that the adduct glycosylation and repair of the single-strand breaks (SSBs) of aged rats are less than those of young rats, although AP endonucleation is sufficient to remove the AP sites. N-nitrosodiethylamine (160 mg/kg, i.p.) increased DNA migration at pH 12.1 and 13 in the liver and kidney at 3 and 24 hr in young rats and at pH 12.1 and 13 in the kidney at 24 hr in aged rats. These results showed that SSBs were predominantly detected as chemical-induced DNA damage and DNA repairs such as N-glycosylase, DNA polymerase and DNA ligase, and that the metabolic activation declined in aged rats. Aspartate aminotransferase, alanine aminotransferase, total bilirubin, total cholesterol, total protein, globulin, creatinine and chloride age-dependently increased and alkaline phosphates, albumin/globulin ratio, inorganic phosphorus and potassium age-dependently decreased, and these changes were correlated with the DNA migration at pH 13 and/or 8-OH-dG. These results suggest that the activity of DNA repair and metabolic activation enzymes declines in aged rats and that the accumulation of spontaneous DNA damage may affect vital functions.
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PMID:DNA damage measured by comet assay and 8-OH-dG formation related to blood chemical analyses in aged rats. 1778 42


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