Silybin supplementation during HCV therapy with pegylated interferon-α plus ribavirin reduces depression and anxiety and increases work ability

Giulia Malaguarnera, Gaetano Bertino, Giuseppe Chisari, Massimo Motta, Michele Vecchio, Marco Vacante, Filippo Caraci, Carmela Greco, Filippo Drago, Giuseppe Nunnari, Michele Malaguarnera, Giulia Malaguarnera, Gaetano Bertino, Giuseppe Chisari, Massimo Motta, Michele Vecchio, Marco Vacante, Filippo Caraci, Carmela Greco, Filippo Drago, Giuseppe Nunnari, Michele Malaguarnera

Abstract

Background: Hepatitis C virus infection and interferon treatment are often associated with anxiety, depressive symptoms and poor health-related quality of life. To evaluate the Silybin-vitamin E-phospholipids complex effect on work ability and whether health related factors (anxiety and depression) were associated with work ability in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b (Peg-IFN) and Ribavirin (RBV).

Methods: Thirty-one patients (Group A) with chronic hepatitis and other 31 subjects in Group B were recruited in a randomized, prospective, placebo controlled, double blind clinical trial. Group A received 1.5 mg/kg per week of Peg-IFN plus RBV and placebo, while Group B received the same dosage of Peg-IFN plus RBV plus association of Silybin 94 mg + vitamin E 30 mg + phospholipids 194 mg in pills for 12 months. All subjects underwent to laboratory exams and questionnaires to evaluate depression (Beck Depression Inventory - BDI), anxiety (State-trait anxiety inventory - STAI) and work ability (Work ability Index - WAI).

Results: The comparison between group A and group B showed significant differences after 6 months in ALT (P < 0.001), and viremia (P < 0.05), after 12 months in ALT (P < 0.001), and AST (P < 0.001), at follow up in AST (P < 0.05), and ALT (P < 0.001). Significant difference were observed after 1 month in WAI (p < 0.001) and BDI (P < 0.05), after 6 months in WAI (P < 0.05) and STAI (P < 0.05), after 12 months and at follow up in WAI, STAI and BDI (p < 0.01).

Conclusions: The supplementation with Silybin-vitamin E -phospholipids complex increased work ability and reduced depression and anxiety in patients treated with Peg-IFN and RBV.

Trial registration: NCT01957319 , First received: September 25, 2013. Last updated: September 30, 2013 (retrospectively registered).

Keywords: Anxiety; Depression; Hepatitis C; Interferon; Silybin; Work ability index.

Figures

Fig. 1
Fig. 1
Trial profile of Peg-IFNα2b plus RBV plus Silybin- Vitamin E- phospholipids treatment

References

    1. Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29(Suppl 1):74–81. doi: 10.1111/j.1478-3231.2008.01934.x.
    1. Kallman J, O’Neil MM, Larive B, Boparai N, Calabrese L, Younossi ZM. Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection. Dig Dis Sci. 2007;52:2531–9. doi: 10.1007/s10620-006-9708-x.
    1. Malaguarnera G, Cataudella E, Giordano M, Nunnari G, Chisari G, Malaguarnera M. Toxic hepatitis in occupational exposure to solvents. World J Gastroenterol. 2012;18(22):2756–66. doi: 10.3748/wjg.v18.i22.2756.
    1. Rapisarda V, Loreto C, Malaguarnera M, Ardiri A, Proiti M, Rigano G, Frazzetto E, Ruggeri MI, Malaguarnera G, Bertino N, Malaguarnera M, Catania VE, Di Carlo I, Toro A, Bertino E, Mangano D, Bertino G. Hepatocellular carcinoma and the risk of occupational exposure. World J Hepatol. 2016;8(13):573–90. doi: 10.4254/wjh.v8.i13.573.
    1. Malaguarnera M, Scuderi L, Ardiri A, Malaguarnera G, Bertino N, Ruggeri IM, Greco C, Ozyalcn E, Bertino E, Bertino G. Type II mixed Cryoglobulinemia in patients with Hepatitis C virus: treatment with Pegylated- Interferon and Ribaverin. Acta Medica Mediterranea. 2015;31:651.
    1. Llansola M, Montoliu C, Agusti A, Hernandez-Rabaza V, Cabrera-Pastor A, Malaguarnera M, Gomez-Gimenez B, Orts A, Garcia-Garcia R, Balzano T, Taoro L, Felipo V. Translational research in hepatic encephalopathy: New diagnostic possibilities and new therapeutic approaches. New Horiz Transl Med. 2015;2(2):39–43. doi: 10.1016/j.nhtm.2014.11.057.
    1. Danzer R, O’connor JC. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56. doi: 10.1038/nrn2297.
    1. Hernández-Rabaza V, Cabrera-Pastor A, Taoro-González L, Malaguarnera M, Agustí A, Llansola M, Felipo V. Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane. J Neuroinflammation. 2016;13:41. doi: 10.1186/s12974-016-0505-y.
    1. Malaguarnera G, Vacante M, Drago F, Bertino G, Motta M, Giordano M, Malaguarnera M. Endozepine-4 levels are increased in hepatic coma. World J Gastroenterol. 2015;21(30):9103–10. doi: 10.3748/wjg.v21.i30.9103.
    1. Malaguarnera G, Pennisi M, Gagliano C, Vacante M, Malaguarnera M, Salomone S, et al. Acetyl-L-Carnitine Supplementation During HCV Therapy With Pegylated Interferon-α 2b Plus Ribavirin: Effect on Work Performance; A Randomized Clinical Trial. Hepat Mon. 2014;14(5):e11608. doi: 10.5812/hepatmon.11608.
    1. Malaguarnera M, Motta M, Vacante M, Malaguarnera G, Caraci F, Nunnari G, Gagliano C, Greco C, Chisari G, Drago F, Bertino G. Silybin-vitamin E-phospholipids complex reduces liver fibrosis in patients with chronic hepatitis C treated with pegylated interferon α and ribavirin. Am J Transl Res. 2015;7(11):2510–8.
    1. Saller R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61:2035–63. doi: 10.2165/00003495-200161140-00003.
    1. Pietrangelo A, Borella F, Casalgrandi G, Montossi G, Ceccarelli D, Gallesi DX, et al. Antioxidant activity of silybin in vivo during long term iron overload in rats. Gastroenterology. 1995;109:1941–9. doi: 10.1016/0016-5085(95)90762-9.
    1. Katiyar SK. Silymarin and skin cancer prevention: anti-inflammatory, antioxidant and immunodelatory effects. Int J Oncol. 2005;26:169–76.
    1. Morazzoni P, Bombardelli E. Silybum marianum (Carduus marianus) Fitoterapia. 1995;64:3–42.
    1. Lu P, Mamiya T, Lu L, Mouri A, Niwa M, Kim HC, et al. Silibinin attenuates cognitive deficits and decreases of dopamine and serotonin induced by repeated methamphetamine treatment. Brain Res. 2010;207(2):387–93.
    1. Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, Hiramatsu M, Ikejima T, Nabeshima T. Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol. 2009;157(7):1270–7. doi: 10.1111/j.1476-5381.2009.00295.x.
    1. Marrazzo G, Bosco P, La Delia F, Scapagnini G, Di Giacomo C, Malaguarnera M, Galvano F, Nicolosi A, Li Volti G. Neuroprotective effect of silibinin in diabetic mice. Neurosci Lett. 2011;504(3):252–6. doi: 10.1016/j.neulet.2011.09.041.
    1. Cabrera-Pastor A, Malaguarnera M, Taoro-Gonzalez L, Llansola M, Felipo V. Extracellular cGMP Modulates Learning Biphasically by Modulating Glycine Receptors, CaMKII and Glutamate-Nitric Oxide-cGMP Pathway. Sci Rep. 2016;6:33124. doi: 10.1038/srep33124.
    1. Du J, Zhu M, Bao H, Li B, Dong Y, Xiao C, Zhang GY, Henter I, Rudorfer M, Vitiello B. The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors. Crit Rev Food Sci Nutr. 2016;56(15):2560–578.
    1. Sayyah M, Boostani H, Pakseresht S, Malayeri A. Comparison of Silybum marianum (L.) Gaertn. with fluoxetine in the treatment of Obsessive-Compulsive Disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:362–5. doi: 10.1016/j.pnpbp.2009.12.016.
    1. Malaguarnera G, Giordano M, Nunnari G, Bertino G, Malaguarnera M. Gut microbiota in alcoholic liver disease: pathogenetic role and therapeutic perspectives. World J Gastroenterol. 2014;20(44):16639–48. doi: 10.3748/wjg.v20.i44.16639.
    1. Li W, Gao J, Zhao HZ, Liu CX. Development of a HPLC-UV assay for silybin-phosphatidylcholine complex (silybinin capsules) and its pharmacokinetic study in healthy male Chinese volunteers. Eur J Drug Metab Pharmacokinet. 2006;31(4):265–70. doi: 10.1007/BF03190466.
    1. World Medical Association declaration of Helsinki Recommendations guiding physicians in biomedical research involving human subjects. JAMA. 1997;277:925–6. doi: 10.1001/jama.1997.03540350075038.
    1. Stuyver L, Wyseur A, van Arnhem W, Hernandez F, Maertens G. Second-generation line probe assay for hepatitis C virus genotyping. J Clin Microbiol. 1996;34:2259–66.
    1. Simmonds P, Alberti A, Alter HJ, Bonino F, Bradley DW, Brechot C, Brouwer JT, et al. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology. 1994;19:1321–4. doi: 10.1002/hep.1840190538.
    1. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1:431–5. doi: 10.1002/hep.1840010511.
    1. Beck A, Steer R, Garbin M. Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clin Psychol Rev. 1988;8:122–32. doi: 10.1016/0272-7358(88)90050-5.
    1. Spielberger CD, Gorsuch RL, Lushene RE. Test manual for the State-Trait Anxiety Inventory. Palo Alto: Consulting Psychologist Press; 1970.
    1. De Zwart B, Frings-Dresen M. Test-retest reliability of the Work Ability Index questionnaire. Occup Med (Lond) 2002;52:177–81. doi: 10.1093/occmed/52.4.177.
    1. Costa G, Goedhard WJA, Ilmarinen J. Assessment and Promotion of Work Ability, Health and Well-Being of Ageing Workers. The Netherlands: Elsevier; 2005. pp. 1–435.
    1. Ilmarinen J, Tuomi K. Past, present and future of work ability. People and Work Research Reports. Finn Inst Occup Health Hels. 2004;65:1–25.
    1. Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007;21(2):153–60. doi: 10.1016/j.bbi.2006.09.006.
    1. Malaguarnera M, Vacante M, Condorelli G, Leggio F, Di Rosa M, Motta M, Malaguarnera G, Alessandria I, Rampello L, Chisari G. Probiotics and prebiotics in the management of constipation in the elderly. Acta Med Mediterr. 2013;29:791–7.
    1. Llansola M, Montoliu C, Agusti A, Hernandez-Rabaza V, Cabrera-Pastor A, Gomez-Gimenez B, Malaguarnera M, Dadsetan S, Belghiti M, Garcia-Garcia R, Balzano T, Taoro L, Felipo V. Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy. Neurochem Int. 2015;88:15–9. doi: 10.1016/j.neuint.2014.10.011.
    1. Zickmund S, Ho EY, Masuda M, Ippolito L, LaBrecque DR. “They treated me like a leper”. Stigmatization and the quality of life of patients with hepatitis C. J Gen Intern Med. 2003;18:835–44. doi: 10.1046/j.1525-1497.2003.20826.x.
    1. Patterson AL, Morasco BJ, Fuller BE, Indest DW, Loftis JM, Hauser P. Screening for depression in patients with hepatitis C using the Beck Depression Inventory-II: do somatic symptoms compromise validity? Gen Hosp Psychiatry. 2011;33(4):354–62. doi: 10.1016/j.genhosppsych.2011.04.005.
    1. Capuron L, Dantzer R. Cytokines and depression: the need for a new paradigm. Brain Behav Immun. 2003;17(Suppl 1):S119–24. doi: 10.1016/S0889-1591(02)00078-8.
    1. Seeff LB. Are herbals as safe as their advocates believe? J Hepatol. 2009;50(1):13–6. doi: 10.1016/j.jhep.2008.10.015.
    1. Seeff LB, Curto TM, Szabo G, Everson GT, Bonkovsky HL, Dienstag JL, Shiffman ML, Lindsay KL, Lok AS, Di Bisceglie AM, Lee WM, Ghany MG, HALT-C Trial Group Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology. 2008;47(2):605–12. doi: 10.1002/hep.22044.
    1. Galvano F, Malaguarnera M, Vacante M, Motta M, Russo C, Malaguarnera G, D’Orazio N, Malaguarnera L. The physiopathology of lipoprotein (a) Front Biosci (Schol Ed) 2010;2:866–75.
    1. Marrazzo G, Barbagallo I, Galvano F, Malaguarnera M, Gazzolo D, Frigiola A, D’Orazio N, Li Volti G. Role of dietary and endogenous antioxidants in diabetes. Crit Rev Food Sci Nutr. 2014;54(12):1599–616. doi: 10.1080/10408398.2011.644874.
    1. Anderson IM, Ferrier IN, Baldwin RC, Cowen PJ, Howard L, Lewis G, Matthews K, McAllister-Williams RH, Peveler RC, Scott J, Tylee A. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2008;22(4):343–96. doi: 10.1177/0269881107088441.
    1. Su J, Brook RA, Kleinman NL, Corey-Lisle P. The impact of hepatitis C virus infection on work absence, productivity, and healthcare benefit costs. Hepatology. 2010;52(2):436–42. doi: 10.1002/hep.23726.
    1. Knekt P, Lindfors O, Laaksonen MA, Raitasalo R, Haaramo P, Järvikoski A, Helsinki Psychotherapy Study Group Effectiveness of short-term and long-term psychotherapy on work ability and functional capacity--a randomized clinical trial on depressive and anxiety disorders. J Affect Disord. 2008;107(1–3):95–106. doi: 10.1016/j.jad.2007.08.005.
    1. Bertino G, Ardiri A, Proiti M, Rigano G, Frazzetto E, Demma S, Ruggeri MI, Scuderi L, Malaguarnera G, Bertino N, Rapisarda V, Di Carlo I, Toro A, Salomone F, Malaguarnera M, Bertino E, Malaguarnera M. Chronic hepatitis C: This and the new era of treatment. World J Hepatol. 2016;8(2):92–106. doi: 10.4254/wjh.v8.i2.92.
    1. Aronsohn A, Jensen D. Interferon-combination strategies for the treatment of chronic hepatitis C. Semin Liver Dis. 2014;34(1):30–6. doi: 10.1055/s-0034-1371008.
    1. Huang M, Jiang JD, Peng Z. Recent advances in the anti-HCV mechanisms of interferon. Acta Pharm Sin B. 2014;4(4):241–7. doi: 10.1016/j.apsb.2014.06.010.
    1. Malaguarnera M, Vacante M, Giordano M, Motta M, Bertino G, Pennisi M, Neri S, Malaguarnera M, Li Volti G, Galvano F. L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-α 2b plus ribavirin. World J Gastroenterol. 2011;17(39):4414–20. doi: 10.3748/wjg.v17.i39.4414.
    1. McHutchison JG, Ware JE, Jr, Bayliss MS, Pianko S, Albrecht JK, Cort S, Yang I, Neary MP, Hepatitis Interventional Therapy Group The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity. J Hepatol. 2001;34(1):140–7. doi: 10.1016/S0168-8278(00)00026-X.
    1. Perrillo R, Rothstein KD, Rubin R, Alam I, Imperial J, Harb G, Hu S, Klaskala W. Comparison of quality of life, work productivity and medical resource utilization of peginterferon alpha 2a vs the combination of interferon alpha 2b plus ribavirin as initial treatment in patients with chronic hepatitis C. J Viral Hepat. 2004;11(2):157–65. doi: 10.1046/j.1365-2893.2003.00482.x.
    1. Fraschini F, Demartini G, Esposti D. Pharmacology of silymarin. Clin Drug Investig. 2002;22:51–65. doi: 10.2165/00044011-200222010-00007.
    1. WenWu J, Lin L, Tsai T. Drug–drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol. 2009;121:185–93. doi: 10.1016/j.jep.2008.10.036.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe