Current Pharmaceutical Design - Volume 6, Issue 2, 2000

Hepatitis C virus (HCV) is responsible for most cases of posttransfusion hepatitis and sporadic or community-acquired non-A, non-B hepatitis.Different generations of enzyme-linked immunosorbent assay have been generated for detecting antibodies to HCV epitopes. HCV-RNA quantitative analysis has been developed by means of polymerase chain reaction technique. This approach is the only reliable method for HCV-RNA tissue localization, being helpful in early diagnosis.HCV infected liver is characterized by an inflammatory infiltrate including CD4positive, CD8positive, and B lymphocytes. Evidence has been provided that in HCV patients CD8positive cell response is associated with low level of viraemia and higher level of disease activity. CD4positive T cells exhibit specificity for the core antigen, also correlating with disease activity and viraemia. Costimulatory molecules, cytokines, oxygen radicals, the complex Fas - Fas-ligand and soluble class I HLA structures are discussed as putative cofactors involved in disease evolution.Various forms of interferon (IFN)-alpha have been evaluated for the treatment of patients with HCV infection. Initial enthusiasm has been attenuated by the evidence of a low sustained virological response rate and the constant side effects of IFN-alpha therapy in patients with chronic HCV disease.Among possible markers for predicting therapeutic outcome in HCV-positive individuals, anti-core antibodies correlate positively with response to IFN-alpha administration, as well as reduction of interleukin-2 serum levels has been detected in patients with a good therapeutic response. Association between HCV infection and autoimmune phenomena, also in relation to IFN-alpha therapy has been reported. Finally, results of the combined treatment with IFN-alpha/ribavirin are illustrated.

Earlier semi-synthetic studies of erythromycin A culminated in the discovery of two successful second generation macrolide antibiotics, azithromycin and clarithromycin, for the treatment of community-acquired bacterial infections. More recent structural modifications of erythromycin A have resulted in the discovery of novel ketolide antibiotics and new motilide prokinetic agents. This review is an account of the semi-synthetic developments from erythromycin A by chemical transformations.

Invasive fungal infections, mainly caused by Candida and Aspergillus species, are an emerging cause of morbidity and mortality among all categories of immunocompromised patients. Currently available antifungal agents, both polyenes, flucytosine and (tri)azoles are hampered by serious infusion- or drug-related toxicity, by hazardous drug-drug interactions, or by pharmacokinetic problems and by the development of resistance, in vitro as well as in vivo. In recent years, several companies have become interested in antifungal drug development and have launched new compounds into preclinical and clinical trials. Some of these agents target the fungal cell wall in stead of the cell membrane. They exert their fungicidal action through inhibition of the synthesis of critical compounds of that fungal cell wall, not present in mammalian cells. Exciting and promising agents include inhibitors of β-(1,3)-D-glucan synthase and inhibitors of chitin synthase. These drugs appear well tolerated in Phase I-II studies and will soon enter Phase III studies. This review wants to provide the clinical framework for assessing the utility of these agents compared to existing antifungals, thereby focusing on invasive fungal disease and emphasising the changing fungal epidemiology and susceptibility in immunocompromised hosts.