Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Forty antiviral compounds were screened for inhibitory effect on hepatitis A virus (HAV) antigen expression in the human hepatoma cell line PLC/PRF/5. Ribavirin, amantadine, glycyrrhizin, and pyrazofurin were selected in this screening test and were studied further. The selectivity indices of these four compounds, calculated as the ratio of 50% cytotoxic dose (determined by the trypan blue exclusion and by inhibition of [3H] leucine incorporation) to the 50% effective dose (determined by the viral antigen expression), were 4.6 and 3.0 with ribavirin, 5.3 and 5.9 with amantadine, 15.2 and 16.9 with glycyrrhizin, and 45.4 and 74.6 with pyrazofurin. All four compounds resulted in concentration-dependent reductions of HAV antigen expression and HAV infectivity. Ribavirin, amantadine, pyrazofurin, and glycyrrhizin emerged, from the present study, as promising candidates for chemotherapy of acute hepatitis A.
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PMID:Inhibition of hepatitis A virus replication in vitro by antiviral compounds. 216 49

Inhibition of IMP dehydrogenase in AS-30D hepatoma cells in suspension culture resulted in a pronounced and selective reduction of guanine nucleotide pools. Total acid-soluble guanine nucleotides decreased to 40% and the content of GTP and GDP dropped to about 20% of control within 4 h when mycophenolate or ribavirin were used as the inhibitors. Induction of GTP deficiency was associated with a 50% rise in UTP and other uracil nucleotides. Guanosine rapidly reversed both the reduction of guanine nucleotide pools and the elevation of cellular UTP contents. Enzymatic nucleotide analyses in cell and tissue extracts after treatment with ribavirin indicated that ribavirin 5'-triphosphate was an effective substrate for yeast hexokinase, yeast phosphoglycerate kinase, and nucleosidediphosphate kinase from yeast or bovine liver. These results were confirmed in detail by the use of synthetic ribavirin 5'-triphosphate and 5'-diphosphate. The latter nucleotide analog was also a substrate of pyruvate kinase from muscle. Mycophenolate-induced GTP deficiency was associated with an arrest of hepatoma cell growth in suspension culture. Ribavirin, at an equimolar concentration, was much less effective in this respect. None of the two inhibitors had a detectable effect, however, in vivo when guanine or uracil nucleotides were assayed in liver. This indicated that an inhibition of de novo guanylate synthesis in vivo can be compensated by salvage pathway synthesis.
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PMID:Selective guanosine phosphate deficiency in hepatoma cells induced by inhibitors of IMP dehydrogenase. 610 11

Interferon alfa, the only treatment currently approved for chronic hepatitis C virus infection, has a limited response rate (20-25%) in most patients. Ribavirin has also been used to treat hepatitis C virus infection, but treatment results in only a modest reduction in HCV-RNA levels; most patients relapse after the drug is discontinued. Combination therapy with ribavirin and interferon seems to be a logical approach to the treatment of hepatitis C virus infection. Small studies suggest that combination therapy results in improved sustained response rates compared with either interferon or ribavirin alone. In one study, 6 months of combination therapy was compared with 6 months of ribavirin monotherapy and 6 months of interferon alfa monotherapy. The sustained virologic response rates were 47% for combination therapy, 13% for interferon monotherapy, and 0% for ribavirin monotherapy. This study suggests that combination therapy can potentially double the sustained response rate, but larger studies are needed to evaluate this further. In trial design for clinical studies, many factors must be considered. Determining the response to interferon monotherapy might include establishing liver histology (especially in patients with cirrhosis) and hepatitis C virus genotype--types 1b and 4 are associated with a poor response, which is likely to affect the response to combination therapy. Patients in treatment trials should be followed long term at regular intervals; it is only with prolonged, detailed follow-up that the full effects of antiviral therapy on health and prevention of cirrhosis and hepatocellular carcinoma can be determined. Large multicenter studies are also needed to determine the effect of combination therapy in liver transplant patients. These studies must also address toxicity issues, as interferon may increase the risk of graft rejection post-transplant, and the low-grade hemolysis associated with ribavirin may stimulate hepatic iron deposition.
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PMID:Future studies of combination therapy for chronic hepatitis C: optimizing response rates for each hepatitis C population. 872 Feb 92

The therapy of viral hepatitis has great medical and socioeconomic impact. Today chronic viral hepatitis is the most important cause for chronic liver disease, liver cirrhosis, and hepatocellular carcinoma. Hepatitis A and E cause acute courses exclusively whereas infection with the hepatitis B, C, and D virus might result in chronic hepatitis as well. The goal of therapy of chronic viral hepatitis has to be a reduction/normalisation of elevated transaminases, decrease of the serologic parameters of active viral replication, improvement of histology and prevention of complications of chronic hepatitis. The only drug with proven benefit in the treatment of chronic viral hepatitis is interferon alpha. This therapy results in a sustained response in 25 to 40% for hepatitis B and 10 to 25% for hepatitis C infection. New developments under clinical evaluation are Lamivudine and Famciclovir in the treatment of HBV-infection and Ribavirin in combination with INFa for chronic HCV-infection.
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PMID:[Therapy of viral hepatitis]. 954 47

Chronic hepatitis C is a major health care problem throughout the world. The disease may progress to cirrhosis, with complications such as hepatocellular carcinoma. The usual primary goal of therapy is viral eradication, as patients with long-term remission are generally regarded as unlikely to develop cirrhosis or hepatocellular carcinoma. Another primary goal should be the reduction in liver fibrosis progression. Interferon-alpha (IFN-alpha) is the only drug approved for the treatment of hepatitis C in Europe and North America. Its effectiveness appears to be related to dose and duration of therapy. The best efficacy/risk ratio seems to be in favour of 3 million units (MU) IFN-alpha three times per week on a 12-month schedule. With this regimen, a sustained alanine aminotransferase (ALT) response is achieved in nearly 35% of patients. Ribavirin has emerged as potentially the second most effective drug. While it appears unsatisfactory when given alone, it seems much more effective in combination with IFN. Combining them seems to exert a synergistic effect between the two drugs and sustained remission might be achieved in nearly 50% of patients with combination therapy. Controversy persists concerning the long-term benefit of therapy in transient responders and non-responders. It is possible that IFN therapy, in comparison to natural history, might reduce liver fibrosis progression and prevent hepatocellular carcinoma, even in non-responders, and have greater efficacy if used in long-term treatment. Whatever the treatment schedule, prolonged viral eradication may not be achieved in all patients and new drugs should be sought to improve the results of therapy.
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PMID:Management of hepatitis C. 957 31

The hepatitis C virus (HCV) shows a pronounced polymorphism with six genotypes and many subtypes. The virus is generally not cytopathogenic. Immunological defence mechanisms are probably essential for the pathogenecity. An acute hepatitis is relatively rare; the infection becomes chronic in over 70%. The data on the occurrence of chronic hepatitis, cirrhosis and hepatocellular carcinoma are conflicting. The age at infection, the gender, coinfections with HBV and HIV and alcohol consumption play a role. The basis of diagnostics is the anti-HCV screening test with clear indications for the measurement of the genotype and of HCV-RNA. The combination of interferon-alpha and Ribavirin is the therapy of choice with improved success. HCV is most often transmitted through contaminated syringes and needles, i.v. drug users having the greatest incidence and prevalence. Vertical and sexual HCV transmission is relatively rare. It is estimated that the HCV prevalence in Switzerland is 0.75-1%, afflicting 50,000-70,000 individuals. Over the next years the number of HCV associated decompensated liver cirrhosis, liver transplantation and death will grow. Efforts of collaboration in the field are undertaken including the establishment of a Swiss HCV cohort study.
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PMID:[Hepatitis C virus infection. Overview. SEVHEP (Swiss Experts on Viral Hepatitis)]. 1108 58

End-stage liver disease due to chronic hepatitis C is the leading indication for orthotopic liver transplantation in the United States. Twenty percent to 30% of hepatitis C patients are at increased risk of developing cirrhosis, and 1% to 4% of cirrhotic patients will develop hepatocellular carcinoma. These findings warrant treatment for hepatitis C virus (HCV)-infected patients. Currently, the mainstay in treatment of HCV is the use of recombinant alpha interferon, or its equivalent, in combination with the oral antiviral agent ribavirin. The major goals of therapy are clearance of the virus, achieving a noninfectious state, and halting the necro-inflammatory process that leads to fibrosis and progression to cirrhosis. End of treatment response (ETR) is biochemical and virological remission-- normalization of serum aminotransferase (ALT) and undetectable levels of HCV RNA, at the end of therapy. Sustained virological response (SVR) is defined as the absence of viremia and persistently normal aminotransferase 6 months off treatment, and is the ultimate goal of therapy. Patients who achieve SVR will have significant and persistent histologic improvement. HCV genotype, pretreatment levels of HCV-RNA (viral load), the presence of advanced fibrosis or cirrhosis, gender, and age are independent predictors of response. Ribavirin is teratogenic, therefore, contraception is mandatory for both males and females during and up to 6 months after therapy. Side effects of combination therapy are dose-dependent and most commonly include symptoms of irritability, depression and fatigue, and laboratory evidences of leukopenia, thrombocytopenia, and hemolytic anemia.
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PMID:Hepatitis C. 1109 32

Hepatitis C is a common infection with worldwide prevalence. It has a variable course and can lead to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Until recently alpha-interferon (IFN-alpha) was the only effective treatment available. Combination therapy with IFN-alpha and ribavirin has been found to be more efficacious than IFN-alpha alone. Various side effects have been ascribed to interferon, such as arthralgias, myalgias, fatigue, and gastrointestinal and neuropsychiatric symptoms. Interstitial pneumonitis is a rare but known complication of IFN-alpha when given at a high dosage of 6 to 10 million units per day. Ribavirin is associated with dose-dependent hemolytic anemia, cough, dyspnea, rash, depression, and dyspepsia, although a potential role in interferon-induced interstitial pneumonitis has not been described. We describe a patient with an excellent clinical response of chronic hepatitis C to combination therapy with IFN-alpha at a dosage of 3 million units per day and ribavirin. The patient developed interstitial pneumonitis that resolved after discontinuation of IFN-alpha and ribavirin. Given that interstitial pneumonitis has previously been reported with high-dose IFN-alpha, this case suggests that this complication may occur with lower dosages of IFN-alpha, although a potential role for ribavirin in this disorder at present remains speculative.
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PMID:Interstitial pneumonitis in a patient treated with alpha-interferon and ribavirin for hepatitis C infection. 1167 22

The hepatitis C virus was first identified in 1989. It causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Global anti-HCV prevalence is 1-3%. Contaminated blood product, dirty needles and instruments, and injection drug use are the main parenteral routes of transmission. Cultural practices, such as acupuncture, tattoo, body piercing and scarring, also play a role. Universal precaution is the mainstay for prevention before vaccine is developed. Therapy for chronic hepatitis C (CHC) with interferon (IFN) is not satisfactory. Non-response and early relapse reduce sustained response (SR). In 1997, National Institute of Health consensus recommended IFN therapy only for selected patients with compensated CHC, raised ALT and moderate to severe histologic disease activity; 15-20% SR is expected. Major advances in CHC therapy is combination therapy. Ribavirin in combination with IFN significantly increases SR to 30-40%. Even patients with high viral load, genotype 1, significant fibrosis or cirrhosis respond better. EASL and APASL Consensus in 1999 recommended IFN-ribavirin combination as the first line therapy. Recent data on pegylated IFN showed very encouraging results. Combined with ribavirin, 60% SR was achieved. It benefits patients with severe bridging necrosis and also cirrhosis. However, 23-27% of patients receiving combination therapy with either IFN type, experienced adverse events and required therapy discontinuation. Many important issues remained unsolved. Therapy for children, the elderly, patients with comorbidity and extra-hepatic syndromes need to be addressed. Therapy is too expensive and not affordable to the majority of patients in developing countries.
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PMID:Management of viral hepatitis C. 1200 Jun

Patients with cirrhosis due to hepatitis C have a high chance of dying from progressive liver disease and thus have much to gain from successful antiviral therapy. The highest sustained virologic responses in patients with cirrhosis have been achieved using pegylated interferon alfa plus Ribavirin; 43% or more remain with undetectable virus 6 months after the cessation of 48 weeks of treatment. In those who achieve a sustained virologic response, the degree of fibrosis is less as judged on posttreatment liver biopsy; cirrhosis may even regress. In those individuals with cirrhosis who achieve a sustained virologic response, the risk of developing hepatocellular carcinoma is significantly reduced and it is likely that their chance of developing liver failure is less. Patients who do not achieve sustained virologic response can still show histologic improvement as demonstrated on liver biopsy posttherapy as compared to baseline. Patients with compensated cirrhosis can benefit from therapy while those who are decompensated are prone to more safety issues. Thus, individuals with any evidence of hepatic decompensation should generally not be given interferon-based antiviral therapy, but treatment should be encouraged for those whose status is Child Class A.
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PMID:Treatment considerations in patients with hepatitis C and cirrhosis. 1456 87


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