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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: Casaubon who wrote (348)	11/9/1999 2:45:00 PM
From: Biomaven	Respond to of 1169

Well ribavirin seems to have quite an effect on the immune system. Note that ALT here decreased only "transiently." J Gen Virol 1998 Oct;79 ( Pt 10):2381-91 Related Articles, LinkOut The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. Hultgren C, Milich DR, Weiland O, Sallberg M Division of Clinical Virology, Huddinge University Hospital, Sweden. Ribavirin is effective in combination therapies against chronic hepatitis C virus (HCV) infection, although its direct antiviral properties are unclear. We therefore studied the immune-modulatory effects of ribavirin on hepatitis B virus (HBV)- and HCV-specific immune responses. During a 24 week placebo-controlled ribavirin trial in ten patients with chronic HCV infection, HCV antibodies and alanine aminotransferase (ALT) levels decreased transiently whereas the serum levels of HCV RNA remained stable. Effects of ribavirin on human and murine phytohaemagglutinin (PHA)-activated T cells included inhibition of in vitro proliferation and modulation of IL-2, IL-4, IFN-gamma and TNF-alpha levels. HBcAg- and HBeAg-specific IL-2 and IFN-gamma levels were > or = 25-fold higher in mice immunized with HBV core- or e-antigens (HBcAg, HBeAg) while receiving ribavirin compared to untreated mice, but IL-4 and IL-6 remained constant. Concordantly, a slight shift was observed in the IgG subclass distribution of the humoral responses of ribavirin-treated mice to HBeAg and HCV NS3 protein. Ribavirin treatment of HBeAg-transgenic (HBeAg-Tg) mice induced a dose-dependent down-regulation of T helper (Th)2-mediated antibody production to HBeAg. In ribavirin-treated HBeAg-Tg mice anti-HBe IgG1 (positively regulated by Th2 cytokines) decreased simultaneously as both anti-HBe IgG2a (positively regulated by Th1 cytokines) levels and in vitro T-cell IFN-gamma production increased, indicating a change in the Th1/Th2 balance. Thus, the present data suggest that ribavirin is not strictly an antiviral compound, but rather it alters the T-cell balance in the immune system.

To: Casaubon who wrote (348)	11/9/1999 11:08:00 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 1169

<<I'm not trying to diminish the achievement of VX-497, just discussing the implications of the data.>> It is always good to have contrarian and/or one who ask questions. As Peter pointed on Ribavirin effects and results on VL in HCV trials, somehow do not have pronounced effects, but in combination with INF do increase pts clinical response even for ones who didn't responded to INF alone and reduce VL (but by unknown mechanisms). VRTX rationale is that potent IMDPH inhibitor like 497 will have similar results. So, they first want to check and confirm sustain ALT level reduction and stabilization (posible impact on VL) over longer period before moving forward with combination trial. So far only INF show reduction in VL, and Rick note on new drugs targeting protease/helicase enzyme is next step. This approach is so hot that anyone from pharma or bts won't talk about. Still, it is far from clinical trials. It means that for now current therapy is best shot and one who can improve drug safety profile will be winner. Miljenko PS: Here are warning paragraph for Ribavirin/Intron and rationale to develop drug with improved safety profile. WARNINGS AND CONTRAINDICATIONS Hemolytic anemia associated with the use of REBETOL in combination with interferon alfa-2b (REBETRON Combination Therapy) may exacerbate symptoms of coronary disease or deteriorate cardiac function. It is advised that complete blood counts (CBC) be obtained at baseline and at week 2 and week 4 of therapy or more frequently if clinically indicated. The most common adverse experiences associated with combination REBETOL/interferon alfa-2b (INTRON A) therapy are ''flu-like'' symptoms, such as headache, fatigue, myalgia and fever, which appear to decrease in severity as treatment continues. Severe psychiatric adverse events may manifest in patients receiving therapy with interferons, including INTRON A therapy. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS AND COMPLETED SUICIDES, MAY OCCUR. Combination REBETOL/INTRON A therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and the six months after stopping therapy. Combination REBETOL/INTRON A therapy should not be initiated until a report of a negative pregnancy has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (two reliable forms) during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embriocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one-twentieth of the recommended human dose of REBETOL. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064.