medigraphic.com
ISSN 1027-2852 (Electronic)
ISSN 0864-4551 (Print)

2017, Number 1

<< Back Next >>

Biotecnol Apl 2017; 34 (1)

Cuban interferon alpha-2b. Thirty years as an effective and safe drug

Nodarse-Cuní H, López-Saura PA

Language: English
References: 72
Page: 1211-1217
PDF size: 432.54 Kb.


ABSTRACT

Since 1986, the Center for Genetic Engineering and Biotechnology of Havana, Cuba, has produced the recombinant human interferon alpha-2b, marketed as Heberon® Alfa R. The therapeutic use of this product has accumulated a high number of researches carried out in the country’s public health network. For the analysis of its safety profile, 28 years of reports of adverse events were reviewed in 5806 individuals, both children and adults, coming from 147 clinical trials or healthy assistances using the product. This review also contains a safety comparison between lyophilized and liquid formulations. In addition, an analysis of the connection between the occurrence of adverse events and the demographic characteristics of the patients, an analysis of immunogenicity and another on the variation of the thyroid function associated to the use of Heberon® Alfa R were included. Finally, a general analysis of the product’s efficacy based on the number of treated patients and the clinical results obtained are presented. Adverse events were reported in 4864 subjects (84 %). The main adverse events were those corresponding to the flu-like syndrome, with higher frequency in male white patients. Hypothyroidism and immunogenicity behaved lower than similar products in the international pharmaceutical market. Approximately 60 % of the treated patients obtained a relevant therapeutic response and a liquid formulation offered a better benefit/ risk ratio. The extensive clinical information evaluated recognizes a Heberon® Alfa R as a safe and effective drug, 30 years after its first production.


REFERENCES

  1. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957;147(927):258-67.

  2. Zhao LJ, He SF, Wang W, Ren H, Qi ZT. Interferon alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus. Cytokine. 2016;80:48-55.

  3. Buxbaum LU. Type I IFNs promote the early IFN-gamma response and the IL-10 response in Leishmania mexicana infection. Parasite Immunol. 2010;32(2):153-60.

  4. Stein BL, Tiu RV. Biological rationale and clinical use of interferon in the classical BCR-ABL-negative myeloproliferative neoplasms. J Interferon Cytokine Res. 2013;33(4):145-53.

  5. Zhang L, Hao CQ, Miao L, Dou XG. Role of Th1/Th2 cytokines in serum on the pathogenesis of chronic hepatitis C and the outcome of interferon therapy. Genet Mol Res. 2014;13(4):9747-55.

  6. Katlinskaya YV, Katlinski KV, Lasri A, Li N, Beiting DP, Durham AC, et al. Type I Interferons Control Proliferation and Function of the Intestinal Epithelium. Mol Cell Biol. 2016;36(7):1124-35.

  7. Rizza P, Moretti F, Belardelli F. Recent advances on the immunomodulatory effects of IFN-alpha: implications for cancer immunotherapy and autoimmunity. Autoimmunity. 2010;43(3):204-9.

  8. Gokce A, Abd Elmageed ZY, Lasker GF, Bouljihad M, Braun SE, Kim H, et al. Intratunical Injection of Genetically Modified Adipose Tissue-Derived Stem Cells with Human Interferon alpha-2b for Treatment of Erectile Dysfunction in a Rat Model of Tunica Albugineal Fibrosis. J Sex Med. 2015;12(7):1533-44.

  9. Liu CC, Gao YJ, Luo H, Berta T, Xu ZZ, Ji RR, et al. Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions. Sci Rep. 2016;6:34356.

  10. Legros L, Guilhot J, Huault S, Mahon FX, Preudhomme C, Guilhot F, et al. Interferon decreases VEGF levels in patients with chronic myeloid leukemia treated with imatinib. Leuk Res. 2014;38(6):662-5.

  11. Chen YC, Liaw YF. Pharmacotherapeutic options for hepatitis B. Expert Opin Pharmacother. 2016;17(3):355-67.

  12. Miyaki E, Hiraga N, Imamura M, Uchida T, Kan H, Tsuge M, et al. Interferon alpha treatment stimulates interferon gamma expression in type I NKT cells and enhances their antiviral effect against hepatitis C virus. PLoS One. 2017;12(3):e0172412.

  13. Foldvari M, Badea I, Kumar P, Wettig S, Batta R, King MJ, et al. Biphasic vesicles for topical delivery of interferon alpha in human volunteers and treatment of patients with human papillomavirus infections. Curr Drug Deliv. 2011;8(3):307-19.

  14. Papan C, Hagl B, Heinz V, Albert MH, Ehrt O, Sawalle-Belohradsky J, et al. Beneficial IFN-alpha treatment of tumorous herpes simplex blepharoconjunctivitis in dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2014;133(5):1456-8.

  15. Kiladjian JJ, Giraudier S, Cassinat B. Interferon-alpha for the therapy of myeloproliferative neoplasms: targeting the malignant clone. Leukemia. 2016;30(4):776-81.

  16. Ismail A, Yusuf N. Type I interferons: key players in normal skin and select cutaneous malignancies. Dermatol Res Pract. 2014;2014:847545.

  17. Shepherd AR, Shepherd E, Brook NR. Intravesical Bacillus Calmette-Guerin with interferon-alpha versus intravesical Bacillus Calmette-Guerin for treating nonmuscle- invasive bladder cancer. Cochrane Database Syst Rev. 2017;3:CD012112.

  18. Rini BI, McDermott DF, Hammers H, Bro W, Bukowski RM, Faba B, et al. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma. J Immunother Cancer. 2016;4:81.

  19. Jimenez-Hernandez E, Duenas-Gonzalez MT, Quintero-Curiel JL, Velasquez- Ortega J, Magana-Perez JA, Berges-Garcia A, et al. Treatment with interferon-alpha- 2b in children with life-threatening hemangiomas. Dermatol Surg. 2008; 34(5):640-7.

  20. Malczewski A, Marshall A, Payne MJ, Mao L, Bafaloukos D, Si L, et al. Intravenous high-dose interferon with or without maintenance treatment in melanoma at high risk of recurrence: meta-analysis of three trials. Cancer Med. 2016;5(1):17-23.

  21. Ingersoll SB, Ahmad S, McGann HC, Banks RK, Stavitzski NM, Srivastava M, et al. Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer. Mol Cell Biochem. 2015;407(1-2):281-7.

  22. Rodriguez JL, Valenzuela C, Marín N, Ferrero J, Ducongé J, Castillo R, et al. Comparative pharmacokinetics and pharmacodynamics of two recombinant human interferon alfa-2b formulations administered intramuscularly in healthy male volunteers. Biotecnol Apl. 2000;17(3):166-70.

  23. Garcia-Garcia I, Gonzalez-Delgado CA, Valenzuela-Silva C, Hernandez-Bernal F, Ferrero-Bibilonia J, Soto-Hernandez R, et al. Bioequivalence of two recombinant interferon alpha-2b liquid formulations in healthy male volunteers. Drugs R D. 2004;5(5):271-80.

  24. Perea SE, Gerónimo H, López-Saura P. Expression of interferon alfa receptors in human tumor cell lines. Correlation with the antiproliferative effect. Acta Científica Venezolana. 1993;44:22-7.

  25. Perea S, Gerónimo H, Vigoa L, Reyes A, López-Saura P. Efecto de interferones alfa y gamma en células tumorales de gliomas en cultivo. Biotecnol Apl. 1991;8:20-31.

  26. Moro A, Santos A, Arana MJ, Perea SE. Activation of the human p27(Kip1) promoter by IFNalpha 2b. Biochem Biophys Res Commun. 2000;269(1):31-4.

  27. Moro A, Perea SE, Pantoja C, Santos A, Arana MD, Serrano M. IFNalpha 2b induces apoptosis and proteasome-mediated degradation of p27Kip1 in a human lung cancer cell line. Oncol Rep. 2001;8(2):425-9.

  28. Lopez-Ocejo O, Perea SE, Bequet-Romero M, Arana MJ, Lopez Saura P. Impaired angiogenic balance and suppression of tumorigenicity in HeLa cells chronically exposed to interferon-alpha. Biochem Biophys Res Commun. 2000;277(2):410-6.

  29. Nodarse-Cuní H, Iznaga-Marín N, Viera- Alvarez D, Rodríguez-Gómez H, Fernández- Fernández H, Blanco-López Y, et al. Interferon alfa-2b as adjuvant treatment of recurrent respiratory papillomatosis in Cuba: National Program (1994-1999 report). J Laryngol Otol. 2004;118:681-7.

  30. Castañeda C, García E, Grá B, Nodarse- Cuní H, García W, Andrade M, et al. Interferon alfa 2b treatment decreases histological activity in children with chronic hepatitis. Acta Gastroenterológica Latinoamericana 2002;32(1):35-42.

  31. Nodarse-Cuní H, Arús-Soler E, Rivera- Reimón LL, Pérez-Lorenzo M, Samada-Suárez M, García-Ferrera WO, et al. Interferon alfa-2b and ribavirin as combined therapy for chronic hepatitis C in Cuba: National Program. Biotecnol Apl. 2012;29:184-8.

  32. Alfonso I, Lopez P, Nodarse H, Toledo MC, Hernández Y. Terapia combinada de criocirugía e interferón alfa-2b humano recombinante frente a criocirugía en el condiloma acuminado. Piel. 2014;(29):536-45.

  33. Garmendia G, Miranda N, Borroso S, Longchong M, Martinez E, Ferrero J, et al. Regression of infancy hemangiomas with recombinant IFN-alpha 2b. J Interferon Cytokine Res. 2001;21(1):31-8.

  34. Rivero J, Fraga M, Cancio I, Cuervo J, Lopez-Saura P. Long-term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals. Biotherapy. 1997;10(2):107-13.

  35. Arús E, Pérez N, Parrilla M, Domínguez C. Efecto antifibrótico del interferon alfa 2b recombinante en la cirrosis hepática por virus B o C. Rev Cubana Med. 2005;44(3-4):1-11.

  36. Astorga R, Cantero O, Contreras D, del Rio-Martin A, Labarta-Beceiro V, Gutierrez- Elvirez A, et al. Intralesional recombinant interferon alpha-2b in Peyronie’s disease. Arch Esp Urol. 2000;53(7):665-71.

  37. Cabrera-Gomez JA, Echazabal-Santana N, Porrero-Martin P, Valenzuela-Silva C, Rodriguez CA, Fuentes-Suarez I, et al. Interferon-alpha2b recombinant improved the cognitive dysfunction in patients with relapsing remitting multiple sclerosis. Rev Neurol. 2003;37(3):214-20.

  38. Cabrera Gomez JA, Cordero Gutierrez JR, Fernandez Lopez O, Reyes Gutierrez B, Romero Garcia K, Simon Consuegra J, et al. Treatment of schizophrenic disorder, paranoid type, with intramuscular recombinant alpha-2b interferon. Biotherapy. 1993;7(1):27-37.

  39. Saura P, Hernandez F, Gonzalez T, Labarta V, Valdes R, Saez V, et al. Interferon alpha- 2b in epidemic neuropathy. Biotecnol Apl. 1995;12(3):188-9.

  40. Páez-Meireles R, Castro-Odio FR, Hernández JR, Torres D, Cosme C, Nodarse H, et al. Increased bioavailability of IFN a 2b modified by chemical conjugation to a two-branched polyethyleneglycol molecule. Biotecnol Apl. 2015;32(3):3521-23.

  41. Garcia-Garcia I, Gonzalez-Delgado CA, Valenzuela-Silva CM, Diaz-Machado A, Cruz-Diaz M, Nodarse-Cuni H, et al. Pharmacokinetic and pharmacodynamic comparison of two “pegylated” interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study. BMC Pharmacol. 2010;10:15.

  42. Garcia-Garcia I, Hernandez-Gonzalez I, Diaz-Machado A, Gonzalez-Delgado CA, Perez-Rodriguez S, Garcia-Vega Y, et al. Pharmacokinetic and pharmacodynamic characterization of a novel formulation containing co-formulated interferons alpha-2b and gamma in healthy male volunteers. BMC Pharmacol Toxicol. 2016;17(1):58.

  43. Tovey MG, Lallemand C. Safety, Tolerability, and Immunogenicity of Interferons. Pharmaceuticals (Basel). 2010;3(4):1162-86.

  44. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255-9.

  45. Bousquet C, Trombert B, Kumar A, Rodrigues JM. Semantic categories and relations for modelling adverse drug reactions towards a categorial structure for pharmacovigilance. AMIA Annu Symp Proc. 2008:61-5.

  46. Venulet J, Bankowski Z. Harmonizing adverse drug reaction terminology: The role of the Council for International Organizations of Medical Sciences. Drug Safety. 1998;19(3):165-72.

  47. González-Cabañas R, Ferrero-Bibilonia J, Morales-Menéndez MG, Aguilera-Rodríguez A, López-Saura P. Antigenicidad del interferón alfa-2b recombinante (Heberon alfa R). Detección de anticuerpos mediante un ensayo inmunoenzimático y neutralización de actividad antiviral. Biotecnol Apl 1998;15(2):71-6.

  48. Ferrero J, Ochagavia ME, Aguilera- Rodríguez A, López-Saura P. Titulación de la actividad antiviral de interferón utilizando el sistema de equipo SUMA. Biotecnol Apl. 1994;11:34-42.

  49. Grossberg SE. Human antibodies to interferons. Report of a National Institutes of Health Workshop held a 26-26 july 1988 in Bethesda, MD. J interferon Res. 1988;8(6):5-7.

  50. Venulet J. The WHO drug monitoring programme: The formative years (1968-1975). In: Bankowski Z, Dunne JF, eds. Drug Surveillance: International Cooperation Past, Present and Future. Geneva: CIOMS, 1994: 13-21.

  51. Pascual I, Betancourt BY, Valenzuela C, López P. Experiencia con las reacciones adversas asociadas con el interferón alfa 2b recombinante en hematología. Rev Cubana Farm. 2005;39(2):1-7.

  52. Dorta Z, Castellanos M, Nodarse H, Arús E, Pérez F, González L. Tolerance to treatment with standard interferon and ribavirin in patients presenting with cirrhosis from hepatitis C. Rev Cubana Med. 2010;49(2):1-10.

  53. Sánchez YA, Arús E, López P, Nodarse H. Safety of recombinant interferon alfa 2b plus ribavirin in chronic hepatitis C. Rev Cubana Farm. 2011:45(1):34-43.

  54. Reznikov LL, Puren AJ, Fantuzzi G, Muhl H, Shapiro L, Yoon DY, et al. Spontaneous and inducible cytokine responses in healthy humans receiving a single dose of IFNalpha2b: increased production of interleukin- 1 receptor antagonist and suppression of IL-1-induced IL-8. J Interferon Cytokine Res. 1998;18(10):897-903.

  55. Baartman TL, Swanepoel T, Barrientos RM, Laburn HP, Mitchell D, Harden LM. Divergent effects of brain interleukin-1ss in mediating fever, lethargy, anorexia and conditioned fear memory. Behav Brain Res. 2017;324: 155-63.

  56. Zhao ZD, Yang WZ, Gao C, Fu X, Zhang W, Zhou Q, et al. A hypothalamic circuit that controls body temperature. Proc Natl Acad Sci U S A. 2017;114(8):2042-7.

  57. Sleijfer S, Bannink M, Van Gool AR, Kruit WH, Stoter G. Side effects of interferon-alpha therapy. Pharm World Sci. 2005;27(6):423-31.

  58. Bodeau S, Lemouel JP, Diouf M, Duverlie G, Nguyen-Khac E, Brochot E. Hemoglobin during ribavirin-based HCV therapy is closely related to circulating levels of DHEA. J Med Virol. 2017;89(6):1033-9.

  59. Kirkwood JM, Bender C, Agarwala S, Tarhini A, Shipe-Spotloe J, Smelko B, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol. 2002;20(17): 3703-18.

  60. Meritet JF, Maury C, Tovey MG. Induction of tolerance to recombinant therapeutic proteins. J Interferon Cytokine Res. 2001;21(12):1031-8.

  61. Weiss K. Safety profile of interferonalpha therapy. Semin Oncol. 1998;25(1 Suppl 1):9-13.

  62. Shen Y, Wang XL, Xie JP, Shao JG, Lu YH, Zhang S, et al. Thyroid Disturbance in Patients with Chronic Hepatitis C Infection: A Systematic Review and Meta-analysis. J Gastrointestin Liver Dis. 2016;25(2):227-34.

  63. Tran HA, Malcolm Reeves GE, Gibson R, Attia JR. Development of thyroid diseases in the treatment of chronic hepatitis C with alpha-interferon may be a good prognosticator in achieving a sustained virological response: a meta-analysis. J Gastroenterol Hepatol. 2009;24(7):1163-8.

  64. Goyal G, Panag K, Garg R. Prevalence of thyroid disorders in hepatitis C virus positive patients on interferon and antiviral therapy. Int J Appl Basic Med Res. 2016;6(4):245-8.

  65. Santana H, Martínez E, Sánchez JC, Moya G, Sosa R, Hardy E. Molecular characterization of recombinant human Interferon Alpha-2b produced in Cuba. Biotecnol Apl. 1999;16(3):154-9.

  66. Singh SK. Impact of product-related factors on immunogenicity of biotherapeutics. J Pharm Sci. 2011;100(2):354-87.

  67. Braun A, Alsenz J. Development and use of enzyme-linked immunosorbent assays (ELISA) for the detection of protein aggregates in interferon-alpha (IFN-alpha) formulations. Pharm Res. 1997;14(10):1394-400.

  68. Garcia I, Bobillo H, Soria Y, Cervantes M, Bermúdez CH, Díaz G, et al. Influence of albumin content and freeze-drying on the immunogenicity of human recombinant Interferon alpha-2b in mice. Biotecnol Apl. 2009;26(4):328-32.

  69. Garcia-Garcia I, Gonzalez-Delgado CA, Valenzuela-Silva C, Hernandez-Bernal F, Ferrero-Bibilonia J, Soto-Hernandez R, et al. Bioequivalence of two recombinant interferon alpha-2b liquid formulations in healthy male volunteers. Drugs R D. 2004;5(5):271-80.

  70. Castellanos-Fernández MI, González- García A, Nodarse-Cuní H, Calzadilla-Bertot L, Martínez-Pérez Y, Sánchez Rodríguez YA, et al. An open, non-controlled clinical study to assess the efficacy and safety of the recombinant human alpha 2b pegylated interferon PEG-Heberon® plus ribavirin for the treatment of chronic hepatitis C virus infection in Cuban patients. Biotecnol Apl. 2015;32:4201-07.

  71. Foster GR. Pegylated interferons for the treatment of chronic hepatitis C: pharmacological and clinical differences between peginterferon-alpha-2a and peginterferonalpha- 2b. Drugs. 2010;70(2):147-65.

  72. Garcia-Vega Y, Garcia-Garcia I, Collazo- Caballero SE, Santely-Pravia EE, Cruz-Ramirez A, Tuero-Iglesias AD, et al. Pharmacokinetic and pharmacodynamic characterization of a new formulation containing synergistic proportions of interferons alpha-2b and gamma (HeberPAG) in patients with mycosis fungoides: an open-label trial. BMC Pharmacol Toxicol. 2012;13:20.




2020     |     www.medigraphic.com