Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primarily resulting as a spin-off of the search for effective anti-HSV or anti-HIV agents, several compounds have been identified as effective and promising candidate anti-HBV drugs, i.e. famciclovir (penciclovir), BMS-200475, lamivudine (3TC), (-)FTC, L(-)Fd4C, L-FMAU, DAPD (DXG), bis(POM)-PMEA and bis(POC)-PMPA. They all inhibit HBV replication in Hep G2 2.2.15 at concentrations that are well below the cytotoxicity threshold. All these nucleoside analogues require three phosphorylation steps to be active, in their triphosphate form, as inhibitors of the HBV DNA polymerase, except for PMEA (adefovir) and PMPA (tenofovir), which need only two phosphorylation steps, to PMEApp and PMPApp, respectively, to interact as chain terminators with the HBV DNA polymerase reaction. Several of these compounds (for example, famciclovir, lamivudine and adefovir) have proven to be efficacious in the duck and/or woodchuck hepatitis models, and, accordingly, famciclovir, lamivudine and adefovir have also proven to be effective (i.e. in reducing HBV DNA levels) in patients with chronic HBV infection. Yet, famciclovir and lamivudine may lead to the emergence of resistance mutations (i.e. L528M and M552V/I) in the HBV DNA polymerase upon long-term treatment. These penciclovir- and lamivudine-resistant HBV mutants still retain susceptibility to adefovir, which, in turn, has so far not been found to engender resistance mutations in HBV. As has become obvious from the experience with the treatment of HIV infections, future HBV chemotherapy may reside in combination drug therapy so as to achieve the highest possible virus reduction, thereby minimizing the likelihood of drug resistance development.
 ...
PMID:Perspectives for the treatment of hepatitis B virus infections. 1041 52

Acyclic nucleoside phosphonates (ANPs) are potent broad-spectrum antivirals, also effective against immunodeficiency viruses and hepatitis viruses. Effects of several ANPs on in vitro cytokine gene expression and nitric oxide (NO) production by murine peritoneal macrophages were investigated. Included in the study were 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; Adefovir), 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; Tenofovir], 9-(S)-[2-(phosphonomethoxy)propyl]adenine; (S)-PMPA), 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP), 9-(R)-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG). Some of them, i.e. (R)-PMPA, (S)-PMPA, and PMEG, stimulate secretion of TNF-alpha and IL-10 in a concentration-dependent manner, and enhance the IFN-gamma-induced secretion of TNF-alpha. Although unable to activate production of nitric oxide (NO) on their own, these compounds substantially augment NO formation induced by IFN-gamma. Analysis of the expression of inducible NO synthase mRNA indicates that the NO-enhancing effect of ANPs is mediated posttranscriptionally. In contrast to IFN-gamma, production of NO triggered by lipopolysaccharide (LPS) alone, or synergistically by LPS+IFN-gamma, remains unaltered by ANPs. The immunomodulatory effects have been differentially expressed in distinct genotypes of inbred strains of mice, including the low NO-responders Balb/c and high NO-responders C3H/HeN. Although less effectively, PMEG and (R)-PMPA also increase production of TNF-alpha and NO by the IFN-gamma- but not LPS-co-stimulated macrophages from C3H/HeJ mice, which are otherwise hypo-responsive to major immune stimuli provided by IFN-gamma and LPS. It can be concluded that the expression of immunomodulatory properties of ANPs depends on the immune state of cells and its activation by distinct priming signals.
 ...
PMID:Macrophage activation by antiviral acyclic nucleoside phosphonates in dependence on priming immune stimuli. 1113 19

Active vaccination against HBV-infection results in a very high protection rate. Therefore, all persons at risk should be vaccinated. Acute HBV-infection seems to progress to chronicity in a minority of adults. Unfortunately, treatment of chronic HBV-infection with interferon and Lamivudine is effective only in about 40% of patients, leading to a complete virus elimination. However, relapse-rates are high. Additionally, mutant viruses arise in the case of Lamivudine treatment (YMDD-mutants). Interestingly, Adefovir, a new nucleoside analogue, seems not to induce virus-mutants, at least after a therapy of 48 weeks. HBV-DNA declines rapidly, transaminases normalize in more than 2/3 of the patients, liver histology improves. As mentioned, active vaccination against HBV is very effective in preventing the infection. Unfortunately, this is not the case in HCV-infection. So far, the development of an HCV-vaccine is mainly hampered due to the variability of the HCV (RNA) virus. Untreated, more than 2/3 of the HCV-infected patients with acute HCV-positive hepatitis develop chronicity. Chronic hepatitis C can be treated preferably with a combination therapy (pegylated interferons + Ribavirin). Sustained response rates average 50 per cent (and more). However, treatment of non-responders as well as the treatment of relapsers remain an unresolved problem.
 ...
PMID:[Hepatitis: associated diseases. Risk groups -- prevention -- treatment]. 1450 91

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.
 ...
PMID:Chronic hepatitis B--treatment with nucleoside analogues. 1610 69

When assessing patients with chronic hepatitis B virus (HBV) infection, consider the state of viral replication, the immune response and whether viral mutations could be present, as well as evidence for liver disease or extrahepatic manifestations. In wild-type infections, loss of hepatitis B e antigen (HBeAg), gain of anti-HBe and disappearance of HBV DNA from serum indicate immunosuppression of viral replication, or 'nonreplicative chronic HBV infection'. This 'healthy carrier' state must be distinguished from HBeAg-negative chronic hepatitis B (CHB) resulting from precore and core promoter mutations. HBeAg-negative CHB is common with genotypes D (Mediterranean region, south Asia) and C (north Asia) infections. Age, disease activity (alanine aminotransferase level) and severity (fibrosis stage, cirrhosis) influence treatment decisions. Following the marginal effectiveness of interferon and often temporary effectiveness of lamivudine due to drug resistance, treatment of CHB is entering a new era. Adefovir, entecavir, tenofovir, telbivudine and clevudine have equal or superior antiviral efficacy to lamivudine, whereas several agents are effective against lamivudine-resistant HBV. Pegylated-interferon (peginterferon) is superior to conventional interferon for obtaining sustained immunosuppression of HBV without drug resistance. Antiviral suppression of HBV replication for 2-5 years reverses hepatic fibrosis, prevents cirrhosis and, when cirrhosis is established, improves liver function, prevents hepatic decompensation and lowers the risk of liver cancer. Before embarking on immunosuppressive chemotherapy or organ transplantation in patients with chronic HBV infection, it is important to start antiviral therapy to prevent hepatitis flares. Antiviral therapy can be effective against membranous glomerulonephritis and polyarteritis nodosa caused by HBV. Further improvements in treatment of CHB are needed to prevent drug resistance and permanently suppress viral replication by eradicating viral templates or stimulating host immune responsiveness to HBV.
 ...
PMID:Management of chronic hepatitis B virus infection: a new era of disease control. 1647 64

Over the last years there has been considerable progress in the treatment of chronic hepatitis B. Five drugs are now approved for the treatment of this virosis: interferon alpha, lamivudine, adefovir, entecavir and telbivudine. Interferons (conventional or PEG) were the first medicine used in the treatment of hepatitis being able to lead the persistent response (loss of DNA-HBV and of AgHbe) to up to one third of treated cases. A large number of nucleoside/nucleotide analogues are, at present, available to treat hepatitis B. The efficacy of lamivudine, the first nucleoside analogue used, is limited by the high rate of resistance. Adefovir has efficacy comparable to that of lamivudine, but with low resistance rate. Entecavir and tenofovir have also been particularly active in the control of hepatitis B virus replication and are associated with minimal resistance development, even during long treatment regimens. Other drugs, such as telbivudine, emtricitabine and clevudine, will become new treatment options in the near future. Individuals co-infected with HIV/HBV are particularly difficult to manage and are nowadays able to benefit from combinations of drugs of the HAART therapy, which should be effective towards both viruses. The development of more potent antiviral drugs as well as new drug combinations, together with a better understanding of hepatitis B virus resistance mechanisms are important milestones to improve treatment efficacy and to diminish, in the future, the global burden of hepatitis B virus.
 ...
PMID:[Advances in the treatment of hepatitis B]. 1787 70

Hepatitis B virus (HBV) infection is the one of the most common causes of the liver diseases in Korea. Since the discovery of Australia antigen (hepatitis associated antigen, or HBsAg later), hepatitis associated antigen was tested widely. HBsAg was detected in 6.6-8.6% in 1980's. Later, it decreased to 5.7% in 1990's. Remarkably, seropositivity of the children deceased to 0.2% after the nationwide vaccination program. Although hepatitis B vaccines are highly effective, the failure rate of perinatal prophylaxis in babies born to HBsAg positive mother was reported to be 4.25%. Treatment of chronic hepatitis B was initiated after the introduction of interferon alpha. Lamivudine opened a new era of oral antiviral agent, and it has been widely used in Korea since 1999. Adefovir was proven to have a good efficacy for lamivudine-resistant chronic hepatitis B. Newer potent antiviral agents such as entecavir, clevudine, and telbivudine are available currently. Further studies are warranted for understanding factors influencing natural history, improving treatment outcomes, and overcoming vaccine non-response.
 ...
PMID:Current status of liver diseases in Korea: hepatitis B. 2003 75