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FW: NATAP: Thalidomide in IFN/RBV Nonresponders

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  • alleypat
    (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
    Message 1 of 2 , Feb 3, 2006
    • 0 Attachment
      (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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    • 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 2 of 2 , Feb 5, 2006
      • 0 Attachment
        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.
        >
        >
        > ----------
        >
        >_______________________________________________
        >NATAP nataphcv mailing list -- nataphcv@...
        >
        >This is an annoucement-only mailing list. Do not reply.
        >
        >To unsubscribe: send a blank email to nataphcv-request@... with a subject of unsubscribe.
        >
        >
        >For more information, see http://seven.pairlist.net/mailman/listinfo/nataphcv
        >
        >_______________________________________________
        >
        >
        >[Non-text portions of this message have been removed]
        >
        >
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