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Re: [GIWorld-Hepatitis] FW: NATAP: Thalidomide in IFN/RBV Nonresponders

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  • avansi7465
    I ve heard enough horror stories about thalidomide that I believe I d pass on that one. So, in short, I agree with you TOTALLY! Anne
    Message 1 of 2 , Feb 5 6:33 PM
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      I've heard enough horror stories about thalidomide that I believe I'd pass on that one. So, in short, I agree with you TOTALLY! Anne

      -----Original Message-----
      >From: alleypat <alleypat@...>
      >Sent: Feb 3, 2006 1:10 PM
      >To: GIWorld-Hepatitis@yahoogroups.com, happyheppers@yahoogroups.com
      >Subject: [GIWorld-Hepatitis] FW: NATAP: Thalidomide in IFN/RBV Nonresponders
      >
      >(Alley's personal comment - I think this company is desparate to find a use
      >for thalidomide. There are a couple of trials for cancer with it and it's
      >not showing much promise and makes people pretty sick)
      >
      >
      >Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to
      >Alfa-Interferon and Ribavirin
      >
      >(Am J Gastroenterol Feb 2006;101:399-402)
      >Case Reports
      >
      >Laura Milazzo, M.D.1, Mara Biasin, Ph.D.2, Nadia Gatti, M.D.1, Luca
      >Piacentini, Ph.D.2, Fosca Niero, M.D.3, Barbara Zanone Poma, Ph.D.1, Massimo
      >Galli, M.D.1, Mauro Moroni, M.D.1, Mario Clerici, M.D.2, and Agostino Riva,
      >M.D.1
      >
      >Immunomodulation of thalidomide is represented by the antiinflammatory
      >effect through inhibition of tumor necrosis factor N1 and costimulatory
      >effect on human CD8+ T cells. We investigated the efficacy and safety of a
      >24-wk course of thalidomide at a dosage of 200 mg/day in eight patients with
      >HCV chronic hepatitis nonresponders to interferon N1 plus ribavirin. We
      >observed a significant mean decrease of serum aminotransferases and
      >N3-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02).
      >Tumor necrosis factor-N1in vitro production in mononuclear cells decreased
      >with thalidomide in all the subjects (p= 0.028). Perforin- and
      >granzyme-specific mRNA expression increased under thalidomide without
      >statistical significance. A positive correlation between biochemical and
      >immunological parameters was observed with higher increase of granzyme and
      >perforin values in patients showing reduction of aminotransferases. Finally
      >upregulation of T-helper 1 cytokine expression as mean interferon N3/IL-10
      >ratio was evidenced. Thalidomide was well tolerated. In conclusion,
      >thalidomide was able to reduce liver enzymes in six out of eight patients
      >with chronic hepatitis C and to reduce tumor necrosis factor N1 production,
      >representing a promising new approach for the treatment of HCV infection.
      >
      >
      >INTRODUCTION
      >
      >The immunopathogenesis of liver damage in chronic hepatitis C is due to
      >cytolytic and noncytolytic mechanisms mediated by cytotoxic T lymphocytes
      >(CTL) and inflammatory cytokines (1, 2). Thalidomide exerts antiinflammatory
      >activity primarily by the inhibition of tumor necrosis factor (TNF)-N1; a
      >potent costimulatory effect of thalidomide on human CD8+ T cells in vitro
      >has been also described (3, 4). Its immunomodulating effects include
      >increased production of IL-12, IL-2, and IFN-N3 (5, 6).
      >
      >We evaluated the safety and the effects of thalidomide in the treatment of
      >eight subjects with HCV chronic hepatitis.
      >
      >PATIENTS AND METHODS
      >
      >Eight HCV-infected patients with active chronic hepatitis, nonresponders or
      >relapsers to a previous treatment with IFN-N1 and ribavirin, were treated
      >with thalidomide at a daily dose of 200 mg for 24 wk. They had no HBV or HIV
      >coinfection and had stopped IFN and ribavirin at least 6 months before
      >enrollment.
      >
      >A liver biopsy was performed within 3 months of enrollment; serum liver
      >enzymes were monitored monthly during the study period and serum
      >quantitative HCV-RNA was measured every 3 months. The study was approved by
      >our Institutional Ethical Committee, a written informed consent was obtained
      >from all the patients.
      >
      >Evaluation of mRNA Specific for Cytolytic Molecules and Cytokines
      >
      >Total RNA was extracted from peripheral blood mononuclear cells (PBMC) and
      >was reverse transcribed. Perforin, granzyme, IL-10, and IFN-N3 were
      >evaluated by RealTime PCR, were expressed as NNCt and presented as ratios
      >between the target gene mRNA and the GAPDH housekeeping mRNA.
      >
      >TNF-N1 Production
      >
      >PBMC were cultured with PMA at a concentration of 1 ng/mL and ionomycin at a
      >concentration of 500 ng/mL for 48 h. TNF-N1 was measured by enzyme-linked
      >immunosorbent assay (ELISA, Amersham Biosciences, UK).
      >
      >Statistical Analysis
      >
      >Continuous data were analyzed by the Student's t-test and by Wilcoxon
      >nonparametric test.
      >
      >RESULTS
      >
      >The characteristics of the patients are shown in Table 1. High prevalence of
      >HCV genotype 1 (75%) and high degree of fibrosis were detected (mean B1
      >standard deviation (SD) Knodell activity score: 6.2 B1 2.4; mean B1 SD
      >Knodell fibrosis score: 4.4 B1 1.5). The mean B1 SD ALT level before
      >thalidomide was 164.9 B1 66 IU/L.
      >
      >Thalidomide was generally well tolerated; the majority of the patients
      >referred constipation and drowsiness and one patient (No. 2) developed mild
      >peripheral neuropathy.
      >
      >We observed a mean decrease of serum ALT of 39% at wk 24 compared to
      >pretreatment levels (from mean value B1 SD of 164.9 B1 66 IU/L to 100.6 B1
      >25 IU/L, p= 0.017 95% CI: 19.1-109.3; Fig. 1A). Gamma-glutamyl-tranferases
      >(GGT) showed a mean decrease of 61% (from mean value B1 SD of 127.6 B1 87
      >IU/L to 49 B1 28 IU/L, p= 0.02; 95% CI: 14.8-128.1 Fig. 1B). Six of the
      >eight patients showed a decrease of serum transaminases, the remaining two
      >did not show significant change of liver enzymes. It is noteworthy that
      >after interruption of thalidomide the mean values of ALT and N3GT returned
      >close to pretreatment levels (Fig. 2).
      >
      >No significant change of serum HCV-RNA was observed.
      >
      >No detectable histologic modification for both necroinflammatory and
      >fibrosis scores was evidenced in the four patients who accepted to undergo
      >liver biopsy at the end of treatment.
      >
      >Immunological Results
      >
      >Granzyme- and perforin-specific mRNA levels increased after 24 wk of
      >thalidomide without reaching statistical significance (Fig. 3A and B). A
      >higher increase of granzyme and perforin values were observed in patients
      >with reduction of ALT: from 3,952 N fold to 6,889 N fold (p= 0.028, 95% CI:
      >691-5176) and from 1,920 N fold to 2,405 N fold (p= 0.46), respectively,
      >while no increase was observed in subjects without biochemical response.
      >Moreover, therapy resulted in an upregulation of Th1 cytokine expression as
      >mean B1 SD IFN-N3/IL-10 ratio changed from 8.1 B1 5 to 13.0 B1 14.7 (p=
      >0.43; Fig. 3C).
      >
      >Finally in vitro TNF-N1 production decreased from a mean B1 SD value of
      >3,530 B1 2,224 pg/mL to 2,397 B1 1,905 pg/mL at wk 24 of treatment. (p=
      >0.028, 95% CI: 170.3-2094.2; Fig. 3D).
      >
      >DISCUSSION
      >
      >To our knowledge this is the first study to employ thalidomide in the
      >treatment of hepatitis C. We observed a significant decrease of ALT and N3GT
      >levels during a 24-wk course of treatment. No effect on HCV viremia and no
      >histological improvement were observed.
      >
      >At the dosage of 200 mg/day thalidomide was well tolerated and no rise of
      >aminotransferases was seen after starting the drug, as previously reported
      >in one patient (7).
      >
      >Interestingly the most significant decrease of ALT was observed in patients
      >with higher pretreatment levels. These data could be explained by the
      >antiinflammatory activity on nonspecific immune activation responsible of
      >liver damage and possibly by the costimulatory effect that thalidomide
      >determines on activated CTL immune response (3, 4, 8).
      >
      >We found an increased IFN-N3/IL-10 mRNA ratio with thalidomide
      >administration, suggesting a cytokine shift from Th2 to Th1, although the
      >limited number of patients and the high individual variability do not allow
      >a conclusive interpretation.
      >
      >A recent study has shown that etanercept, an anti-TNF agent, used as an
      >adjuvant to interferon and ribavirin therapy seems to enhance viral
      >clearance in chronic hepatitis C (9). Several studies have demonstrated the
      >anti-TNF activity of thalidomide in vitro and in vivo and we accordingly
      >detected a reduced TNF-N1 production by stimulated PBMC in vitro. Moreover
      >thalidomide was reported to accelerate the recovery from experimental
      >cirrhosis in rats, probably mediated by TNF-N1 suppression in the liver
      >(10). We did not find histologic improvement in the four follow-up liver
      >specimens, but longer follow-up might be necessary to determine a late
      >beneficial effect.
      >
      >Thalidomide due to its immunomodulatory characteristics might represent a
      >new pharmacologic approach to chronic HCV infection. Future investigations
      >might focus on the association of thalidomide with IFN or possibly with IFN
      >and ribavirin to evaluate the potential improvement of the current
      >therapeutic regimens.
      >
      >
      > ----------
      >
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