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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many nucleoside analogues have been investigated for the treatment of chronic hepatitis B. Some were withdrawn because of significant adverse effects and some are still in the early stage of clinical assessment. Lamivudine has been demonstrated to have consistent efficacy and safety in large-scale, phase III clinical trials. It has achieved a milestone in the treatment of chronic hepatitis B and is now commercially available in many countries. Being a potent inhibitor of hepatitis B viral replication, it achieved around 18% HBeAg seroconversion in HBeAg-positive patients after 1 year of therapy. HBeAg seroconversion is a good endpoint for therapy and has been shown to be 80% durable. The response was better among patients with raised pretreatment alanine aminotransferase levels. Liver necro-inflammation and fibrosis improved significantly after 1 year. Further improvement on extended therapy was observed together with an incremental increase in HBeAg seroconversion. Similar efficacy was demonstrated in HBeAg-negative viraemic patients. The main drawback is the emergence of drug-resistant variants starting from the sixth to ninth month of treatment. This can be associated with varying degrees of relapse of disease activity and may offset the benefit of therapy. With extended therapy, drug-resistant variants continue to emergence at a rate of around 20% per year. Adefovir dipivoxil and entacavir are nucleoside or nucleotide analogues shown to suppress both the wild-type and lamivudine-resistant virus. Combination of these nucleoside/nucleotide analogues with immune modulators may be the answer to eradicate the virus in short-term therapy and avoid the issue of drug resistance.
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PMID:Nucleoside analogues in the treatment of chronic hepatitis B. 1092 83

Better understanding of hepatitis B virus (HBV) replication, natural history and the immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action are the basis for better therapeutic strategies against chronic hepatitis B. Among currently available drugs, interferon-alpha and thymosin-alpha1 have only modest efficacy (approximately 40% vs 9-20% in controls). In the past decade, lamivudine has dominated in the treatment of chronic HBV infection because it is easy to use, safe, and is effective in terms of hepatitis B e antigen and/or HBV-DNA loss, ALT normalization, and improvement in histology. The response rate increases with increasing pretherapy alanine aminotransferase (ALT) levels, suggesting that patients with stronger endogenous immune response against HBV have a better response to direct antiviral agents. Lamivudine is also beneficial in decompensated cirrhotics with HBV replication. Hepatitic flares may occur after stopping lamivudine therapy in nonresponders and also in responders. Therefore, prolonged therapy is usually required. However, tyrosine-methionine-aspartate-aspartate (YMDD) mutations conferring resistance to lamivudine start to emerge after 6-9 months of therapy, and hepatitis flare, even decompensation, may develop after viral breakthrough. Thus the benefits of long-term lamivudine therapy must be balanced against the concern about YMDD mutations and the durability of treatment response. Adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/ nucleotide analogues have shown encouraging results and some agents appear effective in patients with YMDD mutants. Further development of new drugs and new strategies may help to improve treatment in the new century.
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PMID:Therapy of chronic hepatitis B: current challenges and opportunities. 1243 Dec

Lamivudine is a nuleoside analog with potent inhibitory effects on hepatitis B virus (HBV) replication. Prolonged therapy is required for sustained suppression. However, HBV species with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV-RNA-dependent DNA polymerase confering resistance to lamivudine may emerge after 6-9 months therapy with an incidence of 38% and 67% after 2 and 4 years of lamivudine therapy, respectively. During continued lamivudine therapy, patients with YMDD mutant HBV usually show serum alanine aminotransferase (ALT) and HBV-DNA elevations at lower median levels than their baseline. Marked flare of serum ALT or acute exacerbation may occurred as the results of cytotoxic T lymphocyte mediated immune response directed against YMDD mutant. Although viral clearance with or without emergence of distinct lamivudine resistant mutants may occur after such exacerbations, 20% of the exacerbations are complicated with decompensation or even fatality. The exacerbations appear to be more severe than those occur during the natural course of wild type HBV chronic infection. The current practice of continuing lamivudine therapy, therefore, requires careful evaluation. Alternatives include interferon therapy but this seems ineffective. Adefovir dipivoxil and entecavir may effectively suppress the YMDD mutant but these treatments have not yet been available for use. Recent studies have shown no benefit to continuing lamivudine therapy in patients with YMDD mutantions. Before a rescue drug becomes available, the most cost-effective strategy is to select patients with stronger endogenous anti-HBV immunity to increase efficacy and to shorten the duration of lamivudine therapy to avoid the emergence of YMDD mutations.
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PMID:Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. 1247 59

In therapy of chronic hepatitis B, there are new and exciting developments in antivirals such as nucleotide analogues. Adefovir dipivoxil is an oral prodrug of adefovir, a nucleotide analogue of adenosine monophosphate. This agent has a potent in vitro and in vivo effect against herpes virus, retroviruses, and hepadnaviruses. In the hepatitis B virus (HBV) setting, adefovir dipivoxil inhibits both the wild type and lamivudine-resistant HBV strains. The safety profile of adefovir dipivoxil 10 mg is excellent, but higher doses can produce renal tubular damage, particularly when the drug is used for prolonged therapy. Adefovir dipivoxil is an important new addition to the current first-line treatments for HBeAg positive and negative chronic hepatitis B, as well as being rescue therapy for lamivudine-resistant HBV strains. It is also licensed for use in adults with decompensated liver disease, as well as compensated liver disease where there is evidence of active viral replication, persistently elevated serum alanine aminotransferase levels and active liver inflammation and fibrosis. However, a longer follow-up is needed to establish the long term safety and efficacy of adefovir dipivoxil in patients with chronic HBV infection.
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PMID:[Application and efficacy of adefovir dipivoxil in hepatitis B virus-associated chronic liver diseases]. 1464 71

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3,4-DAP; Adefovir dipivoxil, ADL-10-0101, alefacept, alemtuzumab, alosetron hydrochloride, ALT-711, aprepitant, atazanavir sulfate, atlizumab, atvogen; Bortezomib; CETP vaccine, clevudine, crofelemer; DAC:GLP-1, darbepoetin alfa, decitabine, drotrecogin alfa (activated), DX-9065a; E-7010, edodekin alfa, emivirine, emtricitabine, entecavir, erlosamide, erlotinib hydrochloride, everolimus, exenatide; Fondaparinux sodium, frovatriptan, fulvestrant; Gemtuzumab ozogamicin, gestodene; Homoharringtonine, human insulin; Imatinib mesylate, indiplon, indium 111 (111In) ibritumomab tiuxetan, inhaled insulin, insulin detemir, insulin glargine, ivabradine hydrochloride; Lanthanum carbonate, lapatinib, LAS-34475, levetiracetam, liraglutide, lumiracoxib; Maxacalcitol, melagatran, micafungin sodium; Natalizumab, NSC-640488; Oblimersen sodium; Parecoxib sodium, PEG-filgrastim, peginterferon alfa-2(a), peginterferon alfa-2b, pexelizumab, pimecrolimus, pleconaril, pramlintide acetate, pregabalin, prucalopride; rAHF-PFM, Ranelic acid distrontium salt, ranolazine, rDNA insulin, recombinant human soluble thrombomodulin, rhGM-CSF, roxifiban acetate, RSD-1235, rubitecan, ruboxistaurin mesilate hydrate; SC-51, squalamine; Tegaserod maleate, telbivudine, tesaglitazar, testosterone gel, tezosentan disodium, tipranavir; Vatalanib succinate; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate.
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PMID:Gateways to clinical trials. 1467 84

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

Adefovir dipivoxil, an acyclic nucleotide analogue, is effective for the treatment of chronic hepatitis B in both hepatitis B e antigen (HBeAg)-positive and -negative patients, with improvement in liver histology, hepatitis B virus (HBV) DNA levels, alanine aminotransferase levels, and HBeAg seroconversion (for HBeAg-positive patients). It is also effective against lamivudine-resistant strains of hepatitis B mutations. It has been studied in pre- and post-liver transplant patients. Compared to lamivudine, adefovir dipivoxil is associated with a much lower risk of emergence of drug-resistant HBV. Adefovir-associated resistant virus is susceptible to lamivudine therapy. The recommended dose of adefovir dipivoxil 10 mg is associated with low risk of nephrotoxicity. Adefovir dipivoxil can be recommended as a first-line treatment but can also be used in patients with chronic hepatitis B infection who are failing lamivudine therapy.
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PMID:Adefovir dipivoxil in chronic hepatitis B infection. 1550 Mar 83

Only HBV chronically infected patients with ongoing viral replication, high levels of ALT and histological aggressiveness are considered candidates for interferon therapy. The superiority of pegylated interferon over recombinant interferon is remarkable especially in "hard to treat" patients (cirrhosis). Lamivudine therapy is safe and effective in terms of HBV suppression, ALT normalization and improvemet in histology. The emergence of YMDD mutations of HBV during therapy is not only associated with viral and biochemical breakthroug, but hepatitis flared and even hepatic decompensation may also develop. Adefovir dipivoxil demonstrates significant clinical and antiviral benefits in chronic hepatitis B (HBeAg positive and negative), patients with lamivudine-resistant HBV, and pre-as well as post-liver transplantation patients with compensated and decompensated liver function. Current therapy with pegylated interferons and ribavirin is effective in around one-half of previously untreated patients with chronic hepatitis C. Early virological response three months after the beginning of therapy can be used to predict treatment outcome, and therapy can be stopped in those patients who did not become viral undetectable or whose viral level did not decrease by 2-log units or greater. Most patients with HCV infection will develop recurrence after liver transplantation. Combination therapy with interferon and ribavirin are encouraging but limited by the high rate of side effects in the early posttransplat period.
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PMID:[Treatment and prevention of viral hepatitis]. 1591 24

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

Nucleot(s)ide analogues are making milestones in the treatment of chronic hepatitis B (CHB) as safe oral therapy. FDA approved lamivudine in adult patients in 1998, adefovir dipivoxil in 2002, and entecavir in March 2005. Lamivudine is effective in viral suppression, ALT normalization, and improvement in histology in both HBeAg positive and HBeAg negative / HBV DNA positive patients. HBeAg seroconversion rates correlate directly with pretreatment ALT levels at 18-30% after one year of therapy. Hepatitis flares may occur if lamivudine is stopped before HBeAg seroconversion. Lamivudine resistant YMDD mutants emerge at a rate of 15-20% per year of therapy; often associated with the rebound viraemia, relapse of hepatitis or even hepatic decompensation. Durability of response off lamivudine therapy is not satisfactory and may be dependent on duration of therapy post-seroconversion. Lamivudine is well tolerated with few serious adverse events, even in patients with decompensated cirrhosis. Long term therapy in viraemic patients with advanced fibrosis or cirrhosis delays clinical progression. Adefovir dipivoxil is an oral prodrug of adefovir. 10 mg daily is effective in suppressing both wild-type HBV and YMDD mutants, normalising ALT and improving histology. Adefovir dipivoxil has been shown to be well tolerated in longterm therapy. Renal toxicity reported in higher dosages is rarely seen except among patients with creatinine clearance less than 50 ml/min. Adefovir resistance may emerge and the overall rate is much lower than lamivudine, reaching 18% after 4 years of therapy. Adefovir-resistant mutants (rt N236T) are susceptible to lamivudine and entecavir. Little data is available for durability of response off therapy. Entecavir is an oral nucleoside analogue with a recommended dosage of 0.5 mg daily for nucleoside-naive patients, and 1 mg daily for lamivudine-refractory patients. It is a potent antiviral and may also reduced intrahepatitic cccDNA. Entecavir resistance so far has only been detected in lamivudine resistant patients in the one-year studies. Patient counseling is very important to decide on the choice among available therapeutic options. The assessment of the risks/benefits of each option should be carefully explained to individual patient.
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PMID:Chronic hepatitis B--treatment with nucleoside analogues. 1610 69


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