Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

[Guest guest]

Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to

Alfa-Interferon and Ribavirin

(Am J Gastroenterol Feb 2006;101:399-402)

Case Reports

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, 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

α 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 α plus ribavirin. We observed a

significant mean decrease of serum aminotransferases and γ-

glutamyltransferases of 39% and 61%, respectively (p= 0.017 and

0.02). Tumor necrosis factor-αin 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 γ/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 α 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)-α; 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-γ (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-α 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-γ were evaluated by RealTime PCR, were expressed as Π" Π" Ct and

presented as ratios between the target gene mRNA and the GAPDH

housekeeping mRNA.

TNF-α 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-α 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 ± standard deviation (SD) Knodell activity score: 6.2

± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ±

SD ALT level before thalidomide was 164.9 ± 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 ± SD of 164.9 ± 66 IU/L to

100.6 ± 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 ± SD of 127.6 ± 87 IU/L to 49 ± 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 γGT 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

. 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 ± SD IFN-γ/IL-10

ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).

Finally in vitro TNF-α production decreased from a mean ± SD value

of 3,530 ± 2,224 pg/mL to 2,397 ± 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 γGT 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-γ/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-α production by

stimulated PBMC in vitro. Moreover thalidomide was reported to

accelerate the recovery from experimental cirrhosis in rats, probably

mediated by TNF-α 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.

[Guest guest]

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

When I first read this, I noted it as something to talk to my doctor about. Then I checked the web for more data on Thalidomide. This drug was developed by a pharma company, and prior to being banned in the early sixties was used to treat nausia in pregnant women. There were some terrible side effects.

I'm not a pregnant woman, and I try this someday, but I much prefer natural or extracts from naturally occuring substances.

This post is not intended to take away form the validity of 's post, nor the validity of the study being sited. I just wanted to add information to it.

, please continue to post all the good news you find. It not only gives us hope, but shows us that there are thousands of people out there working to help us.

You are an angel ! Bless you and the things you do for us here.

Chris

Eat well, sleep well, be well!

elizabethnv1 wrote:

Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interferon and Ribavirin(Am J Gastroenterol Feb 2006;101:399-402)Case Reports 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, Clerici, M.D.2, and Agostino Riva, M.D.1Immunomodulation of thalidomide is represented by the antiinflammatory effect through inhibition of tumor necrosis factor α 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 α plus ribavirin. We observed a significant mean decrease of serum aminotransferases and γ-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02). Tumor necrosis factor-αin 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 γ/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 α 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)-α; 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-γ (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-α 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 CytokinesTotal RNA was extracted from peripheral blood mononuclear cells (PBMC) and was reverse transcribed. Perforin, granzyme, IL-10, and IFN-γ were evaluated by RealTime PCR, were expressed as ?#34;?#34;Ct and presented as ratios between the target gene mRNA and the GAPDH housekeeping mRNA.TNF-α ProductionPBMC were cultured with PMA at a concentration of 1 ng/mL and ionomycin at a concentration of 500 ng/mL for 48 h. TNF-α was measured by enzyme-linked immunosorbent assay (ELISA, Amersham Biosciences, UK).Statistical AnalysisContinuous 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 ± standard deviation (SD) Knodell activity score: 6.2 ± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ± SD ALT level before thalidomide was 164.9 ± 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 ± SD of 164.9 ± 66 IU/L to 100.6 ± 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 ± SD of 127.6 ± 87 IU/L to 49 ± 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 γGT 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 ResultsGranzyme- and perforin-specific mRNA levels increased after 24 wk of thalidomide without reaching statistical significance (Fig. 3A and . 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 ± SD IFN-γ/IL-10 ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).Finally in vitro TNF-α production decreased from a mean ± SD value of 3,530 ± 2,224 pg/mL to 2,397 ± 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 γGT 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-γ/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-α production by stimulated PBMC in vitro. Moreover thalidomide was reported to accelerate the recovery from experimental cirrhosis in rats, probably mediated by TNF-α 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.It's a pleasure having you join in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/Happy Posting

[Guest guest]

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

When I first read this, I noted it as something to talk to my doctor about. Then I checked the web for more data on Thalidomide. This drug was developed by a pharma company, and prior to being banned in the early sixties was used to treat nausia in pregnant women. There were some terrible side effects.

I'm not a pregnant woman, and I try this someday, but I much prefer natural or extracts from naturally occuring substances.

This post is not intended to take away form the validity of 's post, nor the validity of the study being sited. I just wanted to add information to it.

, please continue to post all the good news you find. It not only gives us hope, but shows us that there are thousands of people out there working to help us.

You are an angel ! Bless you and the things you do for us here.

Chris

Eat well, sleep well, be well!

elizabethnv1 wrote:

Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interferon and Ribavirin(Am J Gastroenterol Feb 2006;101:399-402)Case Reports 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, Clerici, M.D.2, and Agostino Riva, M.D.1Immunomodulation of thalidomide is represented by the antiinflammatory effect through inhibition of tumor necrosis factor α 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 α plus ribavirin. We observed a significant mean decrease of serum aminotransferases and γ-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02). Tumor necrosis factor-αin 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 γ/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 α 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)-α; 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-γ (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-α 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 CytokinesTotal RNA was extracted from peripheral blood mononuclear cells (PBMC) and was reverse transcribed. Perforin, granzyme, IL-10, and IFN-γ were evaluated by RealTime PCR, were expressed as ?#34;?#34;Ct and presented as ratios between the target gene mRNA and the GAPDH housekeeping mRNA.TNF-α ProductionPBMC were cultured with PMA at a concentration of 1 ng/mL and ionomycin at a concentration of 500 ng/mL for 48 h. TNF-α was measured by enzyme-linked immunosorbent assay (ELISA, Amersham Biosciences, UK).Statistical AnalysisContinuous 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 ± standard deviation (SD) Knodell activity score: 6.2 ± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ± SD ALT level before thalidomide was 164.9 ± 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 ± SD of 164.9 ± 66 IU/L to 100.6 ± 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 ± SD of 127.6 ± 87 IU/L to 49 ± 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 γGT 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 ResultsGranzyme- and perforin-specific mRNA levels increased after 24 wk of thalidomide without reaching statistical significance (Fig. 3A and . 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 ± SD IFN-γ/IL-10 ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).Finally in vitro TNF-α production decreased from a mean ± SD value of 3,530 ± 2,224 pg/mL to 2,397 ± 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 γGT 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-γ/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-α production by stimulated PBMC in vitro. Moreover thalidomide was reported to accelerate the recovery from experimental cirrhosis in rats, probably mediated by TNF-α 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.It's a pleasure having you join in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/Happy Posting

[Guest guest]

Thalidomide was used for the nausea of pregnancy over in Europe and motion sickness but it caused devastating birth defects .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

I am using the free version of SPAMfighter for private users.It has removed 19886 spam emails to date.Paying users do not have this message in their emails.Try SPAMfighter for free now!

No virus found in this outgoing message.Checked by AVG Free Edition.Version: 7.1.371 / Virus Database: 267.15.1/250 - Release Date: 2/3/2006

[Guest guest]

was that the only side effects tho? current tx is also very bad

for unborn babies, you have to promise not to get pregnant, OR

get someone pregnant while you are on Interferon and riba....

if it's helpful otherwise maybe they've finally found a good use

for the Thalidomide?

Sara

Re: Thalidomide in the

Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to

her horror stories of taking care of thalidomide babies and the

terrible birth defects . I somehow doubt that thalidomide is ever

going to be used . But as a researcher I am obligated to post

what current research so I did. But I would advocate against this

drug .

------------------------------------------------------------------------------

I am using the free version of SPAMfighter for private users.

It has removed 19886 spam emails to date.

Paying users do not have this message in their emails.

Try SPAMfighter for free now!

It's a pleasure having you join in our conversations. We hope

you have found the support you need with us.

If you are using email for your posts, for easy access to our

group, just click the link--

http://groups.yahoo.com/group/Hepatitis_C_Central/

Happy Posting

[Guest guest]

I took this from the Physicians Desk Reference

WARNING: SEVERE, LIFE-THREATENING HUMAN BIRTH DEFECTS. IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (50 mg)] TAKEN BY A PREGNANT WOMAN DURING HER PREGNANCY CAN CAUSE SEVERE BIRTH DEFECTS. BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE THE CHANCE OF FETAL EXPOSURE TO THALOMID® (thalidomide) AS NEGLIGIBLE AS POSSIBLE, THALOMID® (thalidomide) IS APPROVED FOR MARKETING ONLY UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE "SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S. ™)." UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S. ™ PROGRAM IN ORDER TO RECEIVE PRODUCT. PLEASE SEE THE FOLLOWING BOXED WARNINGS CONTAINING SPECIAL INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM. PRESCRIBERS THALOMID® (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S. ™ program and understand the risk of teratogenicity if thalidomide is used during pregnancy. Major human fetal abnormalities related to thalidomide administration during pregnancy have been documented: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micro pinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented. 1 Mortality at or shortly after birth has been reported at about 40%. 2 Effective contraception (see CONTRAINDICATIONS ) must be used for at least 4 weeks before beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks following discontinuation of thalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal for at least 24 months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential. Before starting treatment , women of childbearing potential should have a pregnancy test (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours prior to beginning therapy. A prescription for thalidomide for a woman of childbearing potential must not be issued by the prescriber until a written report of a negative pregnancy test has been obtained by the prescriber. Male Patients: Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. Once treatment has started , pregnancy testing should occur weekly during the first month of use, then monthly thereafter in women with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy does occur during thalidomide treatment, thalidomide must be discontinued immediately. Any suspected fetal exposure to THALOMID® (thalidomide) must be reported immediately to the FDA via the MedWATCH number at 1-800-FDA-1088 and also to Celgene Corporation. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. FEMALE PATIENTS Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy): she understands and can reliably carry out instructions. she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the System for Thalidomide Education and Prescribing Safety ( S.T.E.P.S. ™) program. she has received both oral and written warnings of the hazards of taking thalidomide during pregnancy and of exposing a fetus to the drug. she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously (see CONTRAINDICATIONS ), unless continuous abstinence from heterosexual sexual contact is the chosen method. (Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential.) she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to starting thalidomide therapy, during thalidomide therapy, and for 4 weeks after stopping thalidomide therapy. she has had a negative pregnancy test with a sensitivity of at least 50 mIU/mL, within the 24 hours prior to beginning therapy. (See PRECAUTIONS , CONTRAINDICATIONS .) if the patient is between 12 and 18 years of age, her parent or legal guardian must have read this material and agreed to ensure compliance with the above.

MALE PATIENTS Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: he understands and can reliably carry out instructions. he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S. ™ program. he has received both oral and written warnings of the hazards of taking thalidomide and exposing a fetus to the drug. he has received both oral and written warnings of the risk of possible contraception failure and of the presence of thalidomide in semen. He has been instructed that he must always use barrier contraception (latex condom) during any sexual contact with women of childbearing potential, even if he has undergone successful vasectomy. he acknowledges, in writing, his understanding of these warnings and of the need to use barrier contraception (latex condom) during any sexual contact with women of childbearing potential, even if he has undergone successful vasectomy. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months) are considered to be women of childbearing potential. if the patient is between 12 and 18 years of age, his parent or legal guardian must have read this material and agreed to ensure compliance with the above.

DESCRIPTION THALOMID® (thalidomide), (alpha)-(N-phthalimido)glutarimide, is an immunomodulatory agent.

CLINICAL PHARMACOLOGY Mechanism of Action Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-(alpha)) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. 3-6 For example, administration of thalidomide has been reported to decrease circulating levels of TNF-(alpha) in patients with ENL, 3 however, it has also been shown to increase plasma TNF-(alpha) levels in HIV-seropositive patients. 7 Pharmacokinetics and Drug Metabolism Absorption The absolute bioavailability of thalidomide from THALOMID® (thalidomide) capsules has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen's disease, the mean time to peak plasma concentrations (T max ) of THALOMID® (thalidomide) ranged from 2.9 to 5.7 hours indicating that THALOMID® (thalidomide) is slowly absorbed from the gastrointestinal tract. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (C max ) increased in a less than proportional manner (see Table 1 below). This lack of C max dose proportionality, coupled with the observed increase in T max values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Coadministration of THALOMID® (thalidomide) with a high fat meal causes minor (<10%) changes in the observed AUC and C max values; however, it causes an increase in T max to approximately 6 hours. Distribution In human blood plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-®- and (-)-(S)- thalidomide. 8 In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen. Metabolism At the present time, the exact metabolic route and fate of thalidomide is not known in humans. Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. In a repeat dose study in which THALOMID® (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism. Elimination As indicated in Table 1 (above) the mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing. As noted in the metabolism subsection, the precise metabolic fate and route of elimination of thalidomide in humans is not known at this time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than 0.7% of the dose excreted in the urine as unchanged drug. Following a single dose, urinary levels of thalidomide were undetectable 48 hrs after dosing. Although thalidomide is thought to be hydrolyzed to a number of metabolites, 9 only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide was identified in the urine of subjects 12 to 24 hours after dosing. Pharmacokinetic Data in Special Populations HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single dose administration of THALOMID® (thalidomide) capsules. Patients with Hansen's Disease: Analysis of data from a small study in Hansen's patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID® (thalidomide). The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown. Patients with Renal Insufficiency: The pharmacokinetics of thalidomide in patients with renal dysfunction have not been determined. Patients with Hepatic Disease: The pharmacokinetics of thalidomide in patients with hepatic impairment have not been determined. Age: Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen's disease ranging in age from 20 to 69 years does not reveal any age-related changes. Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years. Gender: While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values. Race: Pharmacokinetic differences due to race have not been studied. Clinical Studies The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy. Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population. Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide. INDICATIONS AND USAGE THALOMID® (thalidomide) is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID® (thalidomide) is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID® (thalidomide) is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. CONTRAINDICATIONS (See BOXED WARNINGS .) Pregnancy: Category X Due to its known human teratogenicity, even following a single dose, thalidomide is contraindicated in pregnant women and women capable of becoming pregnant. (See BOXED WARNINGS .) When there is no alternative treatment, women of childbearing potential may be treated with thalidomide provided adequate precautions are taken to avoid pregnancy. Women must commit either to abstain continuously from heterosexual sexual contact or to use two methods of reliable birth control, including at least one highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner's vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with thalidomide, during therapy with thalidomide, and continuing for 4 weeks following discontinuation of thalidomide therapy. If hormonal or IUD contraception is medically contraindicated (see also PRECAUTIONS: DRUG INTERACTIONS ), two other effective or highly effective methods may be used. Women of childbearing potential being treated with thalidomide should have pregnancy testing (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours before beginning thalidomide therapy and then weekly during the first month of thalidomide therapy, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy occurs during thalidomide treatment, thalidomide must be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. THALOMID® (thalidomide) is contraindicated in patients who have demonstrated hypersensitivity to the drug and its components. WARNINGS (See BOXED WARNINGS .) Birth defects: Thalidomide can cause severe birth defects in humans. (See BOXED WARNINGS and CONTRAINDICATIONS .) Patients should be instructed to take thalidomide only as prescribed and not to share their thalidomide with anyone else. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. Drowsiness and somnolence: Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery. Peripheral neuropathy: Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common, potentially severe, side effect of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months, however, reports following relatively short-term use also exist. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all. Few reports of neuropathy have arisen in the treatment of ENL despite long-term thalidomide treatment. However, the inability clinically to differentiate thalidomide neuropathy from the neuropathy often seen in Hansen's disease makes it difficult to determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with thalidomide. Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain in the hands and feet. Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy. Consideration should be given to electrophysiological testing, consisting of measurement of sensory nerve action potential (SNAP) amplitudes at baseline and thereafter every 6 months in an effort to detect asymptomatic neuropathy. If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with thalidomide should only be reinitiated if the neuropathy returns to baseline status. Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide. This medication also can cause neutropenia , seizures and a few other less severe effects .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .------------------------------------------------------------------------------ I am using the free version of SPAMfighter for private users. It has removed 19886 spam emails to date. Paying users do not have this message in their emails. Try SPAMfighter for free now! It's a pleasure having you join in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/ Happy Posting

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I took this from the Physicians Desk Reference

WARNING: SEVERE, LIFE-THREATENING HUMAN BIRTH DEFECTS. IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (50 mg)] TAKEN BY A PREGNANT WOMAN DURING HER PREGNANCY CAN CAUSE SEVERE BIRTH DEFECTS. BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE THE CHANCE OF FETAL EXPOSURE TO THALOMID® (thalidomide) AS NEGLIGIBLE AS POSSIBLE, THALOMID® (thalidomide) IS APPROVED FOR MARKETING ONLY UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE "SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S. ™)." UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S. ™ PROGRAM IN ORDER TO RECEIVE PRODUCT. PLEASE SEE THE FOLLOWING BOXED WARNINGS CONTAINING SPECIAL INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM. PRESCRIBERS THALOMID® (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S. ™ program and understand the risk of teratogenicity if thalidomide is used during pregnancy. Major human fetal abnormalities related to thalidomide administration during pregnancy have been documented: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micro pinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented. 1 Mortality at or shortly after birth has been reported at about 40%. 2 Effective contraception (see CONTRAINDICATIONS ) must be used for at least 4 weeks before beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks following discontinuation of thalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal for at least 24 months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential. Before starting treatment , women of childbearing potential should have a pregnancy test (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours prior to beginning therapy. A prescription for thalidomide for a woman of childbearing potential must not be issued by the prescriber until a written report of a negative pregnancy test has been obtained by the prescriber. Male Patients: Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. Once treatment has started , pregnancy testing should occur weekly during the first month of use, then monthly thereafter in women with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy does occur during thalidomide treatment, thalidomide must be discontinued immediately. Any suspected fetal exposure to THALOMID® (thalidomide) must be reported immediately to the FDA via the MedWATCH number at 1-800-FDA-1088 and also to Celgene Corporation. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. FEMALE PATIENTS Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy): she understands and can reliably carry out instructions. she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the System for Thalidomide Education and Prescribing Safety ( S.T.E.P.S. ™) program. she has received both oral and written warnings of the hazards of taking thalidomide during pregnancy and of exposing a fetus to the drug. she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously (see CONTRAINDICATIONS ), unless continuous abstinence from heterosexual sexual contact is the chosen method. (Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential.) she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to starting thalidomide therapy, during thalidomide therapy, and for 4 weeks after stopping thalidomide therapy. she has had a negative pregnancy test with a sensitivity of at least 50 mIU/mL, within the 24 hours prior to beginning therapy. (See PRECAUTIONS , CONTRAINDICATIONS .) if the patient is between 12 and 18 years of age, her parent or legal guardian must have read this material and agreed to ensure compliance with the above.

MALE PATIENTS Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: he understands and can reliably carry out instructions. he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S. ™ program. he has received both oral and written warnings of the hazards of taking thalidomide and exposing a fetus to the drug. he has received both oral and written warnings of the risk of possible contraception failure and of the presence of thalidomide in semen. He has been instructed that he must always use barrier contraception (latex condom) during any sexual contact with women of childbearing potential, even if he has undergone successful vasectomy. he acknowledges, in writing, his understanding of these warnings and of the need to use barrier contraception (latex condom) during any sexual contact with women of childbearing potential, even if he has undergone successful vasectomy. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months) are considered to be women of childbearing potential. if the patient is between 12 and 18 years of age, his parent or legal guardian must have read this material and agreed to ensure compliance with the above.

DESCRIPTION THALOMID® (thalidomide), (alpha)-(N-phthalimido)glutarimide, is an immunomodulatory agent.

CLINICAL PHARMACOLOGY Mechanism of Action Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-(alpha)) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. 3-6 For example, administration of thalidomide has been reported to decrease circulating levels of TNF-(alpha) in patients with ENL, 3 however, it has also been shown to increase plasma TNF-(alpha) levels in HIV-seropositive patients. 7 Pharmacokinetics and Drug Metabolism Absorption The absolute bioavailability of thalidomide from THALOMID® (thalidomide) capsules has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen's disease, the mean time to peak plasma concentrations (T max ) of THALOMID® (thalidomide) ranged from 2.9 to 5.7 hours indicating that THALOMID® (thalidomide) is slowly absorbed from the gastrointestinal tract. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (C max ) increased in a less than proportional manner (see Table 1 below). This lack of C max dose proportionality, coupled with the observed increase in T max values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Coadministration of THALOMID® (thalidomide) with a high fat meal causes minor (<10%) changes in the observed AUC and C max values; however, it causes an increase in T max to approximately 6 hours. Distribution In human blood plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-®- and (-)-(S)- thalidomide. 8 In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen. Metabolism At the present time, the exact metabolic route and fate of thalidomide is not known in humans. Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. In a repeat dose study in which THALOMID® (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism. Elimination As indicated in Table 1 (above) the mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing. As noted in the metabolism subsection, the precise metabolic fate and route of elimination of thalidomide in humans is not known at this time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than 0.7% of the dose excreted in the urine as unchanged drug. Following a single dose, urinary levels of thalidomide were undetectable 48 hrs after dosing. Although thalidomide is thought to be hydrolyzed to a number of metabolites, 9 only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide was identified in the urine of subjects 12 to 24 hours after dosing. Pharmacokinetic Data in Special Populations HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single dose administration of THALOMID® (thalidomide) capsules. Patients with Hansen's Disease: Analysis of data from a small study in Hansen's patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID® (thalidomide). The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown. Patients with Renal Insufficiency: The pharmacokinetics of thalidomide in patients with renal dysfunction have not been determined. Patients with Hepatic Disease: The pharmacokinetics of thalidomide in patients with hepatic impairment have not been determined. Age: Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen's disease ranging in age from 20 to 69 years does not reveal any age-related changes. Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years. Gender: While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values. Race: Pharmacokinetic differences due to race have not been studied. Clinical Studies The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy. Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population. Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide. INDICATIONS AND USAGE THALOMID® (thalidomide) is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID® (thalidomide) is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID® (thalidomide) is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. CONTRAINDICATIONS (See BOXED WARNINGS .) Pregnancy: Category X Due to its known human teratogenicity, even following a single dose, thalidomide is contraindicated in pregnant women and women capable of becoming pregnant. (See BOXED WARNINGS .) When there is no alternative treatment, women of childbearing potential may be treated with thalidomide provided adequate precautions are taken to avoid pregnancy. Women must commit either to abstain continuously from heterosexual sexual contact or to use two methods of reliable birth control, including at least one highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner's vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with thalidomide, during therapy with thalidomide, and continuing for 4 weeks following discontinuation of thalidomide therapy. If hormonal or IUD contraception is medically contraindicated (see also PRECAUTIONS: DRUG INTERACTIONS ), two other effective or highly effective methods may be used. Women of childbearing potential being treated with thalidomide should have pregnancy testing (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours before beginning thalidomide therapy and then weekly during the first month of thalidomide therapy, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy occurs during thalidomide treatment, thalidomide must be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. THALOMID® (thalidomide) is contraindicated in patients who have demonstrated hypersensitivity to the drug and its components. WARNINGS (See BOXED WARNINGS .) Birth defects: Thalidomide can cause severe birth defects in humans. (See BOXED WARNINGS and CONTRAINDICATIONS .) Patients should be instructed to take thalidomide only as prescribed and not to share their thalidomide with anyone else. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. Drowsiness and somnolence: Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery. Peripheral neuropathy: Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common, potentially severe, side effect of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months, however, reports following relatively short-term use also exist. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all. Few reports of neuropathy have arisen in the treatment of ENL despite long-term thalidomide treatment. However, the inability clinically to differentiate thalidomide neuropathy from the neuropathy often seen in Hansen's disease makes it difficult to determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with thalidomide. Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain in the hands and feet. Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy. Consideration should be given to electrophysiological testing, consisting of measurement of sensory nerve action potential (SNAP) amplitudes at baseline and thereafter every 6 months in an effort to detect asymptomatic neuropathy. If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with thalidomide should only be reinitiated if the neuropathy returns to baseline status. Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide. This medication also can cause neutropenia , seizures and a few other less severe effects .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .------------------------------------------------------------------------------ I am using the free version of SPAMfighter for private users. It has removed 19886 spam emails to date. Paying users do not have this message in their emails. Try SPAMfighter for free now! It's a pleasure having you join in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/ Happy Posting

[Guest guest]

I took this from the Physicians Desk Reference

WARNING: SEVERE, LIFE-THREATENING HUMAN BIRTH DEFECTS. IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (50 mg)] TAKEN BY A PREGNANT WOMAN DURING HER PREGNANCY CAN CAUSE SEVERE BIRTH DEFECTS. BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE THE CHANCE OF FETAL EXPOSURE TO THALOMID® (thalidomide) AS NEGLIGIBLE AS POSSIBLE, THALOMID® (thalidomide) IS APPROVED FOR MARKETING ONLY UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE "SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S. ™)." UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S. ™ PROGRAM IN ORDER TO RECEIVE PRODUCT. PLEASE SEE THE FOLLOWING BOXED WARNINGS CONTAINING SPECIAL INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM. PRESCRIBERS THALOMID® (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S. ™ program and understand the risk of teratogenicity if thalidomide is used during pregnancy. Major human fetal abnormalities related to thalidomide administration during pregnancy have been documented: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micro pinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented. 1 Mortality at or shortly after birth has been reported at about 40%. 2 Effective contraception (see CONTRAINDICATIONS ) must be used for at least 4 weeks before beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks following discontinuation of thalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal for at least 24 months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential. Before starting treatment , women of childbearing potential should have a pregnancy test (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours prior to beginning therapy. A prescription for thalidomide for a woman of childbearing potential must not be issued by the prescriber until a written report of a negative pregnancy test has been obtained by the prescriber. Male Patients: Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. Once treatment has started , pregnancy testing should occur weekly during the first month of use, then monthly thereafter in women with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy does occur during thalidomide treatment, thalidomide must be discontinued immediately. Any suspected fetal exposure to THALOMID® (thalidomide) must be reported immediately to the FDA via the MedWATCH number at 1-800-FDA-1088 and also to Celgene Corporation. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. FEMALE PATIENTS Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy): she understands and can reliably carry out instructions. she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the System for Thalidomide Education and Prescribing Safety ( S.T.E.P.S. ™) program. she has received both oral and written warnings of the hazards of taking thalidomide during pregnancy and of exposing a fetus to the drug. she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously (see CONTRAINDICATIONS ), unless continuous abstinence from heterosexual sexual contact is the chosen method. (Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential.) she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to starting thalidomide therapy, during thalidomide therapy, and for 4 weeks after stopping thalidomide therapy. she has had a negative pregnancy test with a sensitivity of at least 50 mIU/mL, within the 24 hours prior to beginning therapy. (See PRECAUTIONS , CONTRAINDICATIONS .) if the patient is between 12 and 18 years of age, her parent or legal guardian must have read this material and agreed to ensure compliance with the above.

MALE PATIENTS Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: he understands and can reliably carry out instructions. he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S. ™ program. he has received both oral and written warnings of the hazards of taking thalidomide and exposing a fetus to the drug. he has received both oral and written warnings of the risk of possible contraception failure and of the presence of thalidomide in semen. He has been instructed that he must always use barrier contraception (latex condom) during any sexual contact with women of childbearing potential, even if he has undergone successful vasectomy. he acknowledges, in writing, his understanding of these warnings and of the need to use barrier contraception (latex condom) during any sexual contact with women of childbearing potential, even if he has undergone successful vasectomy. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months) are considered to be women of childbearing potential. if the patient is between 12 and 18 years of age, his parent or legal guardian must have read this material and agreed to ensure compliance with the above.

DESCRIPTION THALOMID® (thalidomide), (alpha)-(N-phthalimido)glutarimide, is an immunomodulatory agent.

CLINICAL PHARMACOLOGY Mechanism of Action Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-(alpha)) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. 3-6 For example, administration of thalidomide has been reported to decrease circulating levels of TNF-(alpha) in patients with ENL, 3 however, it has also been shown to increase plasma TNF-(alpha) levels in HIV-seropositive patients. 7 Pharmacokinetics and Drug Metabolism Absorption The absolute bioavailability of thalidomide from THALOMID® (thalidomide) capsules has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen's disease, the mean time to peak plasma concentrations (T max ) of THALOMID® (thalidomide) ranged from 2.9 to 5.7 hours indicating that THALOMID® (thalidomide) is slowly absorbed from the gastrointestinal tract. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (C max ) increased in a less than proportional manner (see Table 1 below). This lack of C max dose proportionality, coupled with the observed increase in T max values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Coadministration of THALOMID® (thalidomide) with a high fat meal causes minor (<10%) changes in the observed AUC and C max values; however, it causes an increase in T max to approximately 6 hours. Distribution In human blood plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-®- and (-)-(S)- thalidomide. 8 In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen. Metabolism At the present time, the exact metabolic route and fate of thalidomide is not known in humans. Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. In a repeat dose study in which THALOMID® (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism. Elimination As indicated in Table 1 (above) the mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing. As noted in the metabolism subsection, the precise metabolic fate and route of elimination of thalidomide in humans is not known at this time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than 0.7% of the dose excreted in the urine as unchanged drug. Following a single dose, urinary levels of thalidomide were undetectable 48 hrs after dosing. Although thalidomide is thought to be hydrolyzed to a number of metabolites, 9 only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide was identified in the urine of subjects 12 to 24 hours after dosing. Pharmacokinetic Data in Special Populations HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single dose administration of THALOMID® (thalidomide) capsules. Patients with Hansen's Disease: Analysis of data from a small study in Hansen's patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID® (thalidomide). The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown. Patients with Renal Insufficiency: The pharmacokinetics of thalidomide in patients with renal dysfunction have not been determined. Patients with Hepatic Disease: The pharmacokinetics of thalidomide in patients with hepatic impairment have not been determined. Age: Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen's disease ranging in age from 20 to 69 years does not reveal any age-related changes. Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years. Gender: While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values. Race: Pharmacokinetic differences due to race have not been studied. Clinical Studies The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy. Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population. Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide. INDICATIONS AND USAGE THALOMID® (thalidomide) is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID® (thalidomide) is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID® (thalidomide) is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. CONTRAINDICATIONS (See BOXED WARNINGS .) Pregnancy: Category X Due to its known human teratogenicity, even following a single dose, thalidomide is contraindicated in pregnant women and women capable of becoming pregnant. (See BOXED WARNINGS .) When there is no alternative treatment, women of childbearing potential may be treated with thalidomide provided adequate precautions are taken to avoid pregnancy. Women must commit either to abstain continuously from heterosexual sexual contact or to use two methods of reliable birth control, including at least one highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner's vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with thalidomide, during therapy with thalidomide, and continuing for 4 weeks following discontinuation of thalidomide therapy. If hormonal or IUD contraception is medically contraindicated (see also PRECAUTIONS: DRUG INTERACTIONS ), two other effective or highly effective methods may be used. Women of childbearing potential being treated with thalidomide should have pregnancy testing (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours before beginning thalidomide therapy and then weekly during the first month of thalidomide therapy, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy occurs during thalidomide treatment, thalidomide must be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. THALOMID® (thalidomide) is contraindicated in patients who have demonstrated hypersensitivity to the drug and its components. WARNINGS (See BOXED WARNINGS .) Birth defects: Thalidomide can cause severe birth defects in humans. (See BOXED WARNINGS and CONTRAINDICATIONS .) Patients should be instructed to take thalidomide only as prescribed and not to share their thalidomide with anyone else. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. Drowsiness and somnolence: Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery. Peripheral neuropathy: Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common, potentially severe, side effect of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months, however, reports following relatively short-term use also exist. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all. Few reports of neuropathy have arisen in the treatment of ENL despite long-term thalidomide treatment. However, the inability clinically to differentiate thalidomide neuropathy from the neuropathy often seen in Hansen's disease makes it difficult to determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with thalidomide. Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain in the hands and feet. Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy. Consideration should be given to electrophysiological testing, consisting of measurement of sensory nerve action potential (SNAP) amplitudes at baseline and thereafter every 6 months in an effort to detect asymptomatic neuropathy. If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with thalidomide should only be reinitiated if the neuropathy returns to baseline status. Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide. This medication also can cause neutropenia , seizures and a few other less severe effects .

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .------------------------------------------------------------------------------ I am using the free version of SPAMfighter for private users. It has removed 19886 spam emails to date. Paying users do not have this message in their emails. Try SPAMfighter for free now! It's a pleasure having you join in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/ Happy Posting

[Guest guest]

It was also used in Australia in the 60's. I have a sister who was born with defects that we're assuming was due to this so-called miracle drug back then! Thankfully my sisters birth defects were only minor by comparison with others.

anne

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

[Guest guest]

Oh yes Liz, we know! It affected her spine causing klippel-feil syndrome and scholiosis. Strangely it affected her hand too. She was born without a thumb on one hand. All things considered, yes, she was very lucky.

anne

Re: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interfe

My mother was a nurse in the 60's and I grew up listening to her horror stories of taking care of thalidomide babies and the terrible birth defects . I somehow doubt that thalidomide is ever going to be used . But as a researcher I am obligated to post what current research so I did. But I would advocate against this drug .

[Guest guest]

, YOU are right,, Liz IS an angel!!!Hunter wrote: When I first read this, I noted it as something to talk to my doctor about. Then I checked the web for more data on Thalidomide. This drug was developed by a pharma company, and prior to being banned in the early sixties was used to treat nausia in pregnant women. There were some terrible side effects. I'm not a pregnant woman, and I try this someday, but I much prefer natural or extracts from naturally occuring substances. This post is not intended to take away form the validity of 's post, nor the validity of the study being sited. I just wanted to add information to it. , please continue to post all the good news you find. It not only gives us hope, but shows

us that there are thousands of people out there working to help us. You are an angel ! Bless you and the things you do for us here. Eat well, sleep well, be well! elizabethnv1 wrote: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interferon and Ribavirin(Am J Gastroenterol Feb 2006;101:399-402)Case Reports 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, Clerici, M.D.2, and Agostino Riva, M.D.1Immunomodulation of thalidomide is represented by the antiinflammatory effect through inhibition of tumor necrosis factor α 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 α plus ribavirin. We observed a significant mean decrease of serum aminotransferases and γ-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02). Tumor necrosis factor-αin 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 γ/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 α 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)-α; 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-γ (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-α 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 CytokinesTotal RNA was extracted from peripheral blood mononuclear cells (PBMC) and was reverse transcribed. Perforin, granzyme, IL-10, and IFN-γ were evaluated by RealTime PCR, were expressed as ?#34;?#34;Ct and presented as ratios between the target gene mRNA and the GAPDH

housekeeping mRNA.TNF-α ProductionPBMC were cultured with PMA at a concentration of 1 ng/mL and ionomycin at a concentration of 500 ng/mL for 48 h. TNF-α was measured by enzyme-linked immunosorbent assay (ELISA, Amersham Biosciences, UK).Statistical AnalysisContinuous 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 ± standard deviation (SD) Knodell activity score: 6.2 ± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ± SD ALT level before thalidomide was 164.9 ± 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 ± SD of 164.9 ± 66 IU/L to 100.6 ± 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 ± SD of 127.6 ± 87 IU/L to 49 ± 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 γGT 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 ResultsGranzyme- and perforin-specific mRNA levels increased after 24 wk of

thalidomide without reaching statistical significance (Fig. 3A and . 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 ± SD IFN-γ/IL-10 ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).Finally in vitro TNF-α production decreased from a mean ± SD value of 3,530 ± 2,224 pg/mL to 2,397 ± 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 γGT 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-γ/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-α production by stimulated PBMC in vitro. Moreover thalidomide was reported to accelerate the recovery from experimental cirrhosis in rats, probably mediated by TNF-α 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.It's a pleasure having you join

in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/Happy Posting

[Guest guest]

, YOU are right,, Liz IS an angel!!!Hunter wrote: When I first read this, I noted it as something to talk to my doctor about. Then I checked the web for more data on Thalidomide. This drug was developed by a pharma company, and prior to being banned in the early sixties was used to treat nausia in pregnant women. There were some terrible side effects. I'm not a pregnant woman, and I try this someday, but I much prefer natural or extracts from naturally occuring substances. This post is not intended to take away form the validity of 's post, nor the validity of the study being sited. I just wanted to add information to it. , please continue to post all the good news you find. It not only gives us hope, but shows

us that there are thousands of people out there working to help us. You are an angel ! Bless you and the things you do for us here. Eat well, sleep well, be well! elizabethnv1 wrote: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interferon and Ribavirin(Am J Gastroenterol Feb 2006;101:399-402)Case Reports 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, Clerici, M.D.2, and Agostino Riva, M.D.1Immunomodulation of thalidomide is represented by the antiinflammatory effect through inhibition of tumor necrosis factor α 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 α plus ribavirin. We observed a significant mean decrease of serum aminotransferases and γ-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02). Tumor necrosis factor-αin 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 γ/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 α 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)-α; 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-γ (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-α 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 CytokinesTotal RNA was extracted from peripheral blood mononuclear cells (PBMC) and was reverse transcribed. Perforin, granzyme, IL-10, and IFN-γ were evaluated by RealTime PCR, were expressed as ?#34;?#34;Ct and presented as ratios between the target gene mRNA and the GAPDH

housekeeping mRNA.TNF-α ProductionPBMC were cultured with PMA at a concentration of 1 ng/mL and ionomycin at a concentration of 500 ng/mL for 48 h. TNF-α was measured by enzyme-linked immunosorbent assay (ELISA, Amersham Biosciences, UK).Statistical AnalysisContinuous 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 ± standard deviation (SD) Knodell activity score: 6.2 ± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ± SD ALT level before thalidomide was 164.9 ± 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 ± SD of 164.9 ± 66 IU/L to 100.6 ± 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 ± SD of 127.6 ± 87 IU/L to 49 ± 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 γGT 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 ResultsGranzyme- and perforin-specific mRNA levels increased after 24 wk of

thalidomide without reaching statistical significance (Fig. 3A and . 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 ± SD IFN-γ/IL-10 ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).Finally in vitro TNF-α production decreased from a mean ± SD value of 3,530 ± 2,224 pg/mL to 2,397 ± 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 γGT 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-γ/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-α production by stimulated PBMC in vitro. Moreover thalidomide was reported to accelerate the recovery from experimental cirrhosis in rats, probably mediated by TNF-α 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.It's a pleasure having you join

in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/Happy Posting

[Guest guest]

, YOU are right,, Liz IS an angel!!!Hunter wrote: When I first read this, I noted it as something to talk to my doctor about. Then I checked the web for more data on Thalidomide. This drug was developed by a pharma company, and prior to being banned in the early sixties was used to treat nausia in pregnant women. There were some terrible side effects. I'm not a pregnant woman, and I try this someday, but I much prefer natural or extracts from naturally occuring substances. This post is not intended to take away form the validity of 's post, nor the validity of the study being sited. I just wanted to add information to it. , please continue to post all the good news you find. It not only gives us hope, but shows

us that there are thousands of people out there working to help us. You are an angel ! Bless you and the things you do for us here. Eat well, sleep well, be well! elizabethnv1 wrote: Thalidomide in the Treatment of Chronic Hepatitis C Unresponsive to Alfa-Interferon and Ribavirin(Am J Gastroenterol Feb 2006;101:399-402)Case Reports 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, Clerici, M.D.2, and Agostino Riva, M.D.1Immunomodulation of thalidomide is represented by the antiinflammatory effect through inhibition of tumor necrosis factor α 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 α plus ribavirin. We observed a significant mean decrease of serum aminotransferases and γ-glutamyltransferases of 39% and 61%, respectively (p= 0.017 and 0.02). Tumor necrosis factor-αin 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 γ/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 α 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)-α; 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-γ (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-α 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 CytokinesTotal RNA was extracted from peripheral blood mononuclear cells (PBMC) and was reverse transcribed. Perforin, granzyme, IL-10, and IFN-γ were evaluated by RealTime PCR, were expressed as ?#34;?#34;Ct and presented as ratios between the target gene mRNA and the GAPDH

housekeeping mRNA.TNF-α ProductionPBMC were cultured with PMA at a concentration of 1 ng/mL and ionomycin at a concentration of 500 ng/mL for 48 h. TNF-α was measured by enzyme-linked immunosorbent assay (ELISA, Amersham Biosciences, UK).Statistical AnalysisContinuous 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 ± standard deviation (SD) Knodell activity score: 6.2 ± 2.4; mean ± SD Knodell fibrosis score: 4.4 ± 1.5). The mean ± SD ALT level before thalidomide was 164.9 ± 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 ± SD of 164.9 ± 66 IU/L to 100.6 ± 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 ± SD of 127.6 ± 87 IU/L to 49 ± 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 γGT 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 ResultsGranzyme- and perforin-specific mRNA levels increased after 24 wk of

thalidomide without reaching statistical significance (Fig. 3A and . 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 ± SD IFN-γ/IL-10 ratio changed from 8.1 ± 5 to 13.0 ± 14.7 (p= 0.43; Fig. 3C).Finally in vitro TNF-α production decreased from a mean ± SD value of 3,530 ± 2,224 pg/mL to 2,397 ± 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 γGT 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-γ/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-α production by stimulated PBMC in vitro. Moreover thalidomide was reported to accelerate the recovery from experimental cirrhosis in rats, probably mediated by TNF-α 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.It's a pleasure having you join

in our conversations. We hope you have found the support you need with us. If you are using email for your posts, for easy access to our group, just click the link-- http://groups.yahoo.com/group/Hepatitis_C_Central/Happy Posting