Biological Trace Element Research

, Volume 75, Issue 1–3, pp 53–63 | Cite as

Preliminary study of combination therapy with interferon-α and zinc in chronic hepatitis C patients with genotype 1b

  • Takeaki Nagamine
  • Hitoshi Takagi
  • Hisashi Takayama
  • Akira Kojima
  • Satoru Kakizaki
  • Masatomo Mori
  • Katuyuki Nakajima


We have evaluated the efficacy of interferon-α (IFN-α) plus zinc therapy in hepatitis C patients with genotype 1b, poor responders for IFN alone. Ten patients were injected with 10 MU of IFN-α every day for 4 wk, followed by three times a week for 20 wk (control group). Nine patients took 300 mg of zinc sulfate a day orally during IFN-α therapy (zinc sulfate group), and 15 patients took IFN-α and 150 mg of polaprezinc (polaprezinc group).

On the d 8 of IFN therapy, circadian zinc levels in serum elevated significantly in the polaprezinc group compared to the zinc sulfate group or control group. Serum ALT levels normalized in 73.3% of the polaprezinc group, 55.6% of the zinc sulfate group, and 40.0% of the control group at 6 mo after the end of IFN therapy. Sustained eradication for the hepatitis C virus RNA judged at the end of the 6-mo follow-up period was higher in the polaprezinc group than in the zinc sulfate group (53.3% vs 11.1%, p<0.05) or the control group (20.0%). No clinical side effects of zinc were observed at the dose used. The data suggest that polaprezinc is expected to increase the therapeutic response of IFN-α for chronic hepatitis C with genotype 1b.

Index Entries

Chronic hepatitis C polaprezinc interferon-α HCV RNA 


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  1. 1.
    G. L. Davis, L. A. Balart, E. R. Schiff, K. Lindsay, H. C. Bodenheimer, Jr., R. P. Perrillo, et al., Treatment of chronic hepatitis C with recombinant interferon alpha: a multicenter, randomized, controlled trial, N. Engl. J. Med. 321, 1501–1506 (1989).PubMedCrossRefGoogle Scholar
  2. 2.
    A. M. Di Bisceglie, P. Martin, C. Kassianides, M. Lisker-Melman, L. Murray, J. Waggoner, et al., Recombinant interferon alfa therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial, N. Engl. J. Med. 321, 1506–1510 (1989).PubMedCrossRefGoogle Scholar
  3. 3.
    M. Shindo, A. Di Bisceglie, and J. Hoofnagel, Long term follow-up of patients with chronic hepatitis C treated with alfa-interferon, Hepatology 45, 1013–1016 (1992).CrossRefGoogle Scholar
  4. 4.
    M. L. Shiffman, C. M. Hofmann, V. A. Luketic, A. J. Sanyal, M. J. Contos, and A. S. Mills, Improved sustained response following treatment of chronic hepatitis C by gradual reduction in the interferon dose, Hepatology 24, 21–26 (1996).PubMedCrossRefGoogle Scholar
  5. 5.
    K. L. Lindsay, G. L. Davis, E. R. Shiff, H. C. Bodenheimer, L. A. Balart, J. L. Dienstag, et al., Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial, Hepatology 24, 1034–1040 (1996).PubMedGoogle Scholar
  6. 6.
    J. Y. Lau, G. L. Davis, J. Kniffen, K. P. Qian, M. S. Urdea, C. S. Chan, et al., Significance of serum hepatitis C virus RNA levels in chronic hepatitis, Lancet 341, 1501–1504 (1993).PubMedCrossRefGoogle Scholar
  7. 7.
    N. N. Zein and D. H. Persing, Hepatitis C genotypes: current trends and future implications, Mayo. Clin. Proc. 71, 458–462 (1993).CrossRefGoogle Scholar
  8. 8.
    G. Rasi, D. DiVirgilio, M. G. Mutchnick, F. Colella, P. Sinibaldi-Vallebona, P. Piermarchi, et al., Combination thymosin alpha 1 and lymphoblastoid interferon treatment in chronic hepatitis C, Gut 39, 679–683 (1996).PubMedGoogle Scholar
  9. 9.
    O. Reichard, R. Schvarcz, and O. Weiland, Therapy of hepatitis C: alpha interferon and ribavirin, Hepatology 26(Suppl. 1), 108S-111S (1997).PubMedCrossRefGoogle Scholar
  10. 10.
    F. Farinati, R. Cardin, N. De Maria, G. Della Libera, C. Marafin, E. Lecis, et al., Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis, J. Hepatol. 22, 449–456 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    J. K. Olynyk, K. R. Reddy, A. M. Di Bisceglie, L. J. Jeffers, T. I. Parker, J. L. Radick, et al., Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C, Gastroenterology 108, 1104–1109 (1995).PubMedCrossRefGoogle Scholar
  12. 12.
    A. Piperno, M. Sampietro, R. D’Alba, L. Roffi, S. Fargion, S. Parma, et al., Iron stores, response to alpha-interferon therapy, and effects of iron depletion in chronic hepatitis C, Liver 16, 248–254 (1996).PubMedGoogle Scholar
  13. 13.
    O. Beloqui, J. Prieto, M. Suarez, B. Gil, C. H. Qian, N. Garcia, et al., N-Acetyl cysteine enhances the response to interferon-αlfa in chronic hepatitis C: a pilot study, J. Interferon Res. 13, 279–282 (1993).PubMedGoogle Scholar
  14. 14.
    R. J. Cousins, Absorption, transport and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin, Physiol. Rev. 65, 238–309 (1985).PubMedGoogle Scholar
  15. 15.
    P. M. Hanna, M. B. Kadiiska, S. J. Jordan, and R. P. Mason, Role of metallothionein in zinc and chromium mediated tolerance to carbon tetrachloride hepatotoxicity: evidence against a trichloromethyl radical scavenging mechanism, Chem. Res. Toxicol. 6, 711–717 (1993).PubMedCrossRefGoogle Scholar
  16. 16.
    M. Sato, J. Yamaki, T. Oguro, T. Yoshida, N. Nomura, and K. Nakajima, Induction of metallothionein synthesis by interferon α/β in response to zinc in mice, Tohoku J. Exp. Med. 178, 241–250 (1996).PubMedCrossRefGoogle Scholar
  17. 17.
    B. D. Korant and B. E. Butterworth, Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc with capsid polypeptides, J. Virol. 18, 298–306 (1976).PubMedGoogle Scholar
  18. 18.
    Y. J. Gordon, Y. Asher, and Y. Becker, Irreversible inhibition of herpes simplex virus and procapsid synthesis by zinc ions, Antimicrob. Agents Chemother. 8, 377–380 (1975).PubMedGoogle Scholar
  19. 19.
    E. Katz and E. Margalith, Inhibition of vaccina virus maturation by zinc chloride, Antimicrob. Agents Chemother. 19, 213–217 (1981).PubMedGoogle Scholar
  20. 20.
    M. Ratka, M. Lackmann, C. Ueckermann, U. Karlins, and G. Koch, Poliovirus-associated protein kinase: destabilization of the virus capsid and stimulation of the phosphorylation reaction by Zn2+, J. Virol. 63, 3954–3960 (1989).PubMedGoogle Scholar
  21. 21.
    Z. Y. Zhang, I. M. Reardon, J. O. Hui, K. L. O’Connell, R. A. Poorman, A. G. Tomasselli, et al., Zinc inhibition of renin and the protease from human immunodeficiency virus type 1, Biochemistry 10, 8717–8721 (1991).CrossRefGoogle Scholar
  22. 22.
    B. Yoffe, S. Pollack, E. Ben-Porath, O. Zinder, D. Barzilai, and H. Gershon, Natural killer cell activity in post-necrotic cirrhotic patients as related to hepatitis-B virus infection and plasma zinc levels, Immunol. Lett. 14, 15–19 (1986).PubMedCrossRefGoogle Scholar
  23. 23.
    C. Driessen, K. Hirv, L. Rink, and H. Kirchner, Induction of cytokines by zinc ions in human peripheral mononuclear cells and separated monocytes, Lymphokine Cytokine Res. 13, 15–20 (1994).PubMedGoogle Scholar
  24. 24.
    D. E. Poswillo and B. Cohen, Inhibition of carcinogenesis by dietary zinc, Nature 231, 447–448 (1971).PubMedCrossRefGoogle Scholar
  25. 25.
    T. Nagamine, H. Takagi, Y. Hashimoto, H. Takayama, R. Shimoda, N. Nomura, et al., The possible role of zinc and metallothionein in the liver on the therapeutic effect of interferon-αlpha to hepatitis C patients, Biol. Trace Element Res. 58, 65–76 (1997).Google Scholar
  26. 26.
    H. Sano, S. Furuta, S. Totama, M. Miwa, Y. Ikeda, M. Suzuki, et al., Study on the metabolic fate of catena-(S)-[μ[N a-(3-aminopropionyl) histidinate(2-)-N 1,N 2,O:N τ]-zinc], Drug Res. 41(II), 965–975 (1991).Google Scholar
  27. 27.
    A. Miyoshi, H. Matsuo, G. Miwa, and M. Nakajima, Clinical evaluation of Z-103 in the treatment of gastric ulcer, Jpn. Pharmacol. Ther. 20, 181–197 (1992).Google Scholar
  28. 28.
    T. Yoshikawa, Y. Naito, T. Tanigawa, T. Yoneta, and M. Kondo, The antioxidant properties of a novel zinc-carnosine chelate compound, N-(3-aminopropionyl)-l-histidinate zinc, Biochem. Biophys. Acta 115, 15–22 (1991).Google Scholar
  29. 29.
    H. Okamoto, Y. Sugiyama, S. Okada, K. Kurai, Y. Akahane, Y. Sugai, et al., Detection of hepatitis C virus RNA typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing infectious sources, J. Gen. Virol. 73, 673–679 (1992).PubMedCrossRefGoogle Scholar
  30. 30.
    S. Karacyclin, A. Arcasoy, and O. Uzunalimoglu, Zinc plasma levels after oral zinc tolerance test in non-alcoholic cirrhosis, Dig. Dis. Sci. 30, 329–333 (1985).CrossRefGoogle Scholar
  31. 31.
    G. Fernandes, M. Nair, K. Onoe, T. Tanaka, R. Flyd, and R. A. Good, Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice, Proc. Natl. Acad. Sci. USA 70, 457–461 (1979).CrossRefGoogle Scholar
  32. 32.
    M. Dardenne, J. M. Pleau, B. Nabarra, P. Lefrancier, D. M. Derrien, J. Choay, et al., Contribution of zinc and other metals to the biological activity of the serum thymic factor, Proc. Natl. Acad. Sci. USA 79, 5370–5373 (1982).PubMedCrossRefGoogle Scholar
  33. 33.
    R. Kohen, Y. Yamamoto, K. C. Cundy, and B. N. Ames, Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain, Proc. Natl. Acad. Sci. USA 85, 3175–3179 (1988).PubMedCrossRefGoogle Scholar
  34. 34.
    O. I. Arouma, M. J. Laughton, and B. Halliwell, Carnosine, homocarnosine and anserine: could they act as antioxidants in vivo? Biochem. J. 264, 863–869 (1989).Google Scholar
  35. 35.
    G. J. Fosmire, Zinc toxicity, Am. J. Clin. Nutr. 51, 225–227 (1990).PubMedGoogle Scholar
  36. 36.
    H. H. Sandstead, Requirements and toxicity of essential trace elements, illustrated by zinc and copper, Am. J. Clin. Nutr. 61, 621S-624S (1995).PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2000

Authors and Affiliations

  • Takeaki Nagamine
    • 1
  • Hitoshi Takagi
    • 2
  • Hisashi Takayama
    • 2
  • Akira Kojima
    • 2
  • Satoru Kakizaki
    • 2
  • Masatomo Mori
    • 2
  • Katuyuki Nakajima
    • 3
  1. 1.Department of Health ScienceGunma University School of MedicineMaebashiJapan
  2. 2.First Department of Internal MedicineGunma University School of MedicineMaebashiJapan
  3. 3.Otsuka America Pharmaceutical, Inc.Rockville

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