thymosin and Hepatitis-C

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of thymosin alpha-1 (TA1) are reviewed. TA1 is a synthetic polypeptide. The drug is in Phase III trials for the treatment of hepatitis C and in Phase II trials for hepatitis B. Additional possible indications are malignant melanoma, hepatocellular carcinoma, drug-resistant tuberculosis, and DiGeorge's syndrome. TA1 is thought to modulate the immune system by augmenting T-cell function. TA1 may affect thymocytes by stimulating their differentiation or by converting them to active T cells. TA1 is rapidly absorbed, achieving peak serum concentrations within two hours. Blood levels return to baseline within 24 hours, and the serum half-life is approximately 2 hours. TA1's efficacy in hepatitis B has been evaluated in 195 patients in four clinical trials. One study found hepatitis B virus (HBV) DNA clearance at six months in 9 of 17 patients receiving TA1, compared with 10 of 16 patients treated with interferon alfa-2b (IFN-alpha 2b) and 4 of 15 historical controls. An open-label trial found HBV DNA clearance in 53% of patients at six months. A randomized, controlled trial found HBV DNA clearance in 40.6% and 25.6% of patients treated with TA1 for 6 and 12 months, respectively, compared with 9.4% of untreated controls. Efficacy for hepatitis C has been evaluated in 162 patients in three clinical trials. In one trial, the number of patients who achieved normal serum alanine aminotransferase (ALT) levels did not differ significantly between TA1 and placebo. In the other two trials, combination TA1 and IFN-alpha 2b was compared with IFN-alpha 2b alone. One trial found a normal serum ALT level at six months in 71% of patients receiving combination therapy, versus 35% of patients receiving IFN-alpha 2b alone. Hepatitis C virus RNA clearance occurred in 65% of patients treated with combination therapy and 29% of patients treated with IFN-alpha 2b alone. The third trial, comparing combination TA1 and IFN-alpha 2b with IFN-alpha 2b alone and with placebo, found normalization of ALT levels at six months in 37.1% of patients receiving combination therapy, 16.2% of patients receiving IFN-alpha 2b alone, and 2.7% of patients receiving placebo. TA1 is well tolerated. Most studies observed only local irritation at the injection site. For hepatitis B and C, TA1 1.6 mg (900 micrograms/m2) should be administered subcutaneously twice a week. Clinical trials of TA1 for chronic h

Topics: Adjuvants, Immunologic; Biological Availability; Education, Pharmacy, Continuing; Hepatitis B; Hepatitis C; Humans; Orphan Drug Production; Randomized Controlled Trials as Topic; Thymalfasin; Thymosin

Topics: Antiviral Agents; Chronic Disease; Drug Therapy, Combination; Hepatitis C; Humans; Interferons; Randomized Controlled Trials as Topic; Ribavirin; Thymosin

At the present time, interferon is considered the only effective therapeutic approach in the treatment of both chronic hepatitis B and chronic hepatitis C. It is clear that the disappointing response rates in both chronic hepatitis B and C place added emphasis on efforts to identify alternative forms of therapy. In addition to the development of other antiviral agents including the nucleoside analogs which might prove more effective and have fewer associated side-effects, other agents currently under investigation include thymic peptides such as thymosin alpha 1. In the future, the therapeutic approach to the treatment of chronic hepatitis B and C may consist of combination therapy using perhaps an immune modulator and an antiviral agent or, several antiviral drugs. Alternatively, there is indication that cellular targeting systems with delivery of the toxic material to the specific cell containing the virus may be more effective, while minimizing side-effects. Finally, there are agents such as ursodeoxycholic acid which perhaps, makes bile less toxic and can be used as adjunctive therapy with improvement in liver chemistry values. The treatment of chronic hepatitis B and chronic hepatitis C has shifted in emphasis form the concept of treating liver disease towards that of treating viral infections which happen to effect primarily the liver.

Topics: Adjuvants, Immunologic; Antiviral Agents; Bile Acids and Salts; Chronic Disease; Hepatitis B; Hepatitis C; Humans; Interferons; Nucleosides; Peptides; Thymosin; Thymus Gland

A randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy and safety of thymosin alpha 1 (alpha 1) in treating chronic hepatitis C. Nineteen Italian patients with chronic active hepatitis C, proven by biopsy were randomly assigned to receive a six month course of thymosin alpha 1 (900 micrograms/m2 of body surface area twice weekly) or a placebo. All had HCV-RNA in their serum (by PCR), with serum ALT levels more than double the upper limit of the normal range for at least six months before enrollment. After treatment, patients were followed for an additional six months. All patients completed the trial. One patient treated with thymosin alpha 1, but no patient in the placebo group, normalized serum ALT levels by the end of the treatment. This patient, however, relapsed at the sixth month of the follow up. Overall, there were no significant changes in mean serum ALT levels in either group during the treatment or follow-up period. No patient cleared HCV-RNA. No side effects were reported except for local discomfort at the injection sites, reported by some patients treated with thymosin alpha 1. In conclusion, this regimen of thymosin alpha 1 is not effective in the treatment of chronic hepatitis C.

Topics: Adult; Alanine Transaminase; Antiviral Agents; Female; Hepacivirus; Hepatitis C; Humans; Italy; Male; Middle Aged; RNA, Viral; Thymalfasin; Thymosin

Despite tremendous efforts in disclosing the pathophysiological and epidemiological factors associated with liver fibrogenesis, non-invasive diagnostic measures to estimate the clinical outcome and progression of liver fibrogenesis are presently limited. Therefore, there is a mandatory need for methodologies allowing the reasonable and reliable assessment of the severity and/or progression of hepatic fibrogenesis. We here performed proteomic serum profiling by matrix-assisted laser desorption ionization time-of-flight mass spectrometry in 179 samples of patients chronically infected with hepatitis C virus and 195 control sera. Multidimensional analysis of spectra allowed the definition of algorithms capable to distinguish class-specific protein expression profiles in serum samples. Overall about 100 peaks could be detected per single spectrum. Different algorithms including protein peaks in the range of 2000 and 10,000 Da were generated after pre-fractionation on a weak cation exchange surface. A specificity of 93% with a sensitivity of 86% as mean of the test set results was found, respectively. The nature of three of these protein peaks that belonged to kininogen-1 and thymosin-β(4) was further analysed by tandem mass spectrometry (MS)/MS. We further found that kininogen-1 mRNA was significantly down-regulated in cirrhotic livers. We have identified kininogen-1 and thymosin-β(4) as potential new biomarkers for human chronic hepatitis C and conclude that serum profiling is a reliable technique to identify hepatitis-associated expression patterns. Based on the high throughput capability, the identified differential protein panel may serve as a diagnostic marker and warrants further validation in larger cohorts.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Child; Female; Hepatitis C; Humans; Kininogens; Liver; Liver Cirrhosis; Male; Middle Aged; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thymosin; Young Adult

Interferon alpha2b (IFNalpha2b) and thymosin alpha1 (Talpha1) exhibit synergic effects in the treatment of hepatitis B and hepatitis C when used together. For developing a fusion protein drug, fusion proteins of IFNalpha2b and Talpha1 linked by different lengths of (G4S)n (n = 1-3) were constructed and expressed in Pichia pastoris.. Using PCR and molecular clone techniques, the fusion genes of IFNalpha2b-(G4S)n-Talpha1 (n = 1-3) were constructed and subcloned into the eukaryotic expression vector pPIC9. After transformation of these plasmids into P. pastoris, the expressed fusion proteins IFNalpha2b-(G4S)n-Talpha1 (n = 1-3) were obtained. These proteins were purified through diethylaminoethyl (DEAE) affinity chromatography and Superdex 75 gel filtration and analyzed by SDS-PAGE and Western blot. Antiviral and E-rosette assays were used to investigate the bioactivities of these fusion proteins.. DNA sequencing confirmed that the fusion genes of IFNalpha2b-(G4S)n-Talpha1 (n = 1-3) were correctly cloned to the pPIC9 vector. The recombinant IFNalpha2b-(G4S)n-Talpha1 (n = 1-3) fusion proteins expressed in P. pastoris were purified with DEAE and Superdex 75 gel filtration chromatography. The fusion proteins could be observed on sodium dodecylsulfate-polyacrylamide gel electrophoresis with molecular weight (MW) of 23.2, 22.9, and 22.6 ku, respectively, and reacted to the IFNalpha2b monoclonal antibody and Talpha1 polyclonal antibody. The purified fusion proteins exhibit antiviral activity and can enhance the percentage of E-rosette-forming-cell in E-rosette assay.. The recombinant IFNalpha2b-(G4S)n-Talpha1 (n = 1-3) fusion proteins were successfully expressed in P. pastoris. Purified fusion proteins exhibit both antiviral activity of IFNalpha2b and immunomodulatory activity of Talpha1 in vitro. These results will be the basis for further evaluation of the fusion proteins' function in vivo.

Topics: Drug Design; Hepatitis B; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Pichia; Plasmids; Recombinant Fusion Proteins; Recombinant Proteins; Thymalfasin; Thymosin

Identification of gene products exclusively or abundantly expressed in cancer may yield novel tumour markers. We recently isolated a number of cDNA clones, including alpha-prothymosin, from rat hepatocellular carcinoma (HCC) using a subtraction-enhanced display technique. Alpha-Prothymosin is involved in cell proliferation and is regulated by the oncogene c-myc in vitro. In the present study, we analysed alpha-prothymosin gene expression and its correlation with c-myc in patients with HCC, cirrhosis and adenoma and in normal controls. Hepatic alpha-prothymosin messenger RNA (mRNA) levels were two- to 9.2-fold higher in tumoral tissues than in adjacent non-tumoral tissues in 14 of 17 patients with HCC, regardless of coexisting cirrhosis and viral hepatitis. No marked difference in alpha-prothymosin mRNA levels was present in patients with adenoma and hepatic cirrhosis and in healthy controls. The c-myc mRNA amounts were two- to fivefold increased in 11 of 17 patients with HCC and correlated significantly with those of alpha-prothymosin (P < 0.001). In situ hybridization revealed that increased alpha-prothymosin mRNA was localized in the tumour nodules of the patients with HCC. These data suggest that overexpression of alpha-prothymosin in HCC patients, correlated with c-myc, is possibly involved in the tumorigenic process and may be a novel molecular marker for human HCC.

Topics: Adenoma; Adult; Aged; Biomarkers, Tumor; Blotting, Northern; Carcinoma, Hepatocellular; Female; Hepatitis B; Hepatitis C; Humans; In Situ Hybridization; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Protein Precursors; Proto-Oncogene Proteins c-myc; Radioimmunoassay; RNA, Messenger; Thymosin

Topics: Chemotherapy, Adjuvant; Hepatitis C; Hepatitis, Chronic; Humans; Interferon-alpha; Thymalfasin; Thymosin

Monotherapy for chronic hepatitis C using interferon (IFN) results in a very small proportion of patients exhibiting a sustained response. Clinical trials assessing the benefit of combination drug therapy may provide evidence of improved treatment response over that seen with single drug treatment.. To assess the response in patients with chronic hepatitis C to one year of combination treatment: thymosin alpha 1 (T alpha 1), 1 mg twice weekly, and lymphoblastoid (L)-IFN, 3 MU thrice weekly.. Fifteen patients with serum HCV RNA positive chronic hepatitis C were studied. Eleven patients were treatment naive and four had failed previous standard IFN therapy. Thirteen patients were HCV RNA serotype 1b. All patients were given combination T alpha 1 and L-IFN therapy for one year with a six month follow up period.. Six months after initiation of treatment seven patients (47%) were sera HCV RNA negative and at completion of the one year treatment 11 (73%), including two who had failed previous standard IFN treatment, had negative serum HCV RNA. Six months after treatment, six patients (40%), including five with HCV type 1b, showed a sustained response characterized by a negative serum HCV RNA.. The results of this open label trial suggest that there may be a potential benefit to combining an immune modulator (T alpha 1) with an antiviral (IFN) in the treatment of chronic hepatitis C. Verification of the observations in this study require completion of a randomised controlled study.

Topics: Adult; Aged; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C; Hepatitis, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Polymerase Chain Reaction; RNA, Viral; Thymalfasin; Thymosin