FROM LEGACY TO INNOVATION: PIDOTIMOD’S EXPANDING THERAPEUTIC HORIZON Pidotimod: Revisiting a Classic Immunomodulator
Main Article Content
Keywords
Immunomodulation, Recurrent Infections, Immunotherapy, Oral Immunomodulators, Adjunct Therapy
Abstract
Pidotimod, a synthetic dipeptide, has been utilized for over three decades as an immunomodulatory agent to prevent recurrent respiratory infections, particularly in immunocompromised populations such as children and the elderly. Originally developed for its ability to enhance innate and adaptive immune responses, pidotimod is now being revisited in light of new clinical insights and emerging therapeutic needs.
Recent studies have expanded its potential beyond traditional indications, with evidence supporting its role in patients with chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), allergic rhinitis, and even viral infections, including SARS-CoV-2. Pidotimod exerts its effects by stimulating dendritic cells, enhancing toll-like receptor (TLR) expression, and promoting cytokine production, including IL-2 and IFN-γ, thereby supporting both cellular and humoral immunity. This broad-spectrum immune modulation makes pidotimod a promising adjunct in managing immune-mediated diseases and infections in both immunocompetent and immunocompromised individuals.
In this review, we examine pidotimod's pharmacodynamics, summarize clinical evidence from recent studies, and explore its evolving role in modern therapeutic strategies for infectious diseases. Given its safety profile and oral administration, pidotimod holds significant promise not only for preventing infections but also as part of a broader immunomodulatory approach in complex disease management.
Downloads
Abstract 69
PDF Downloads 19
HTML Downloads 11
References
[2] J. Liu, X. Zhang, Y. Cheng, and X. Cao, Dendritic cell migration in inflammation and immunity. Cell Mol Immunol 18 (2021) 2461-2471.
[3] C. Ucciferri, J. Vecchiet, and K. Falasca, Role of monoclonal antibody drugs in the treatment of COVID-19. World J Clin Cases 8 (2020) 4280-4285.
[4] L. Amaya-Uribe, M. Rojas, G. Azizi, J.M. Anaya, and M.E. Gershwin, Primary immunodeficiency and autoimmunity: A comprehensive review. J Autoimmun 99 (2019) 52-72.
[5] K.S. Tuano, N. Seth, and J. Chinen, Secondary immunodeficiencies: An overview. Ann Allergy Asthma Immunol 127 (2021) 617-626.
[6] D. Spotti, M. Biffi, G. Coppi, S. Silingardi, and F. Mailland, Pharmacokinetics of pidotimod in elderly volunteers and in renal failure patients. Arzneimittelforschung 44 (1994) 1470-2.
[7] F. Mailland, G. Coppi, and S. Silingardi, Pharmacokinetics and oral bioavailability of pidotimod in humans. Arzneimittelforschung 44 (1994) 1465-9.
[8] G. Migliorati, L. D'Adamio, G. Coppi, I. Nicoletti, and C. Riccardi, Pidotimod stimulates natural killer cell activity and inhibits thymocyte cell death. Immunopharmacol Immunotoxicol 14 (1992) 737-48.
[9] S. Oddera, M. Silvestri, O. Sacco, C. Eftimiadi, and G.A. Rossi, [Effect of pidotimod on phagocytosis and intracellular killing of Staphylococcus aureus by human circulating polymorphonuclear neutrophils and alveolar macrophages]. Drugs Exp Clin Res 19 Suppl (1993) 27-35.
[10] C. Giagulli, M. Noerder, M. Avolio, P.D. Becker, S. Fiorentini, C.A. Guzman, and A. Caruso, Pidotimod promotes functional maturation of dendritic cells and displays adjuvant properties at the nasal mucosa level. Int Immunopharmacol 9 (2009) 1366-73.
[11] G.A. Rossi, C. Peri, M.E. Raynal, A.C. Defilippi, F.M. Risso, G. Schenone, E. Pallestrini, and G. Melioli, Naturally occurring immune response against bacteria commonly involved in upper respiratory tract infections: analysis of the antigen-specific salivary IgA levels. Immunol Lett 86 (2003) 85-91.
[12] F. Caccuri, A. Bugatti, S. Corbellini, S. Roversi, A. Zani, P. Mazzuca, S. Marsico, A. Caruso, and C. Giagulli, The Synthetic Dipeptide Pidotimod Shows a Chemokine-Like Activity through CXC Chemokine Receptor 3 (CXCR3). Int J Mol Sci 20 (2019).
[13] T. Wu, J. Cui, J. Gao, H. Zhou, A. Li, and W. Guo, Pidotimod enhanced the anti-growth effect of cisplatin on lung cancer in mice via promoting anti-tumor immune response. Biochem Biophys Res Commun 528 (2020) 678-684.
[14] W. Zhang, J. Huang, H. Liu, X. Wen, Q. Zheng, and L. Li, Whether Immunostimulants Are Effective in Susceptible Children Suffering From Recurrent Respiratory Tract Infections: A Modeling Analysis Based on Literature Aggregate Data. J Clin Pharmacol 62 (2022) 245-253.
[15] A. Mahashur, P.K. Thomas, P. Mehta, K. Nivangune, S. Muchhala, and R. Jain, Pidotimod: In-depth review of current evidence. Lung India 36 (2019) 422-433.
[16] E. Clemente, R. Solli, V. Mei, R. Cera, G. Caramia, V. Carnelli, E. Ruffini, V. Venturoli, and A. Corsini, Therapeutic efficacy and safety of pidotimod in the treatment of urinary tract infections in children. Arzneimittelforschung 44 (1994) 1490-4.
[17] R. Hu, C. Jin, X. Lin, Y. Chen, Y. Wang, and Y. Guo, Analysis of Factors and T-Lymphocyte Subset Changes in Pediatric Recurrent Respiratory Infections Post-Pidotimod Treatment. Altern Ther Health Med 31 (2025) 470-475.
[18] M.J. Kulashree Charusheila Pramod Walavalkar, Mahendra Kelkar, Suhas Kulkarni, Vijay Tuteja, Francesco Scarci, Efficacy and safety of pidotimod as adjuvant in the treatment of recurrent upper respiratory tract infections (URTI) in children. Trends in Medicine 14 (2016) 11-16.
[19] L.S. Namazova-Baranova, A.A. Alekseeva, S.M. Kharit, T.N. Kozhevnikova, T.E. Taranushenko, I.A. Tuzankina, and F. Scarci, Efficacy and safety of pidotimod in the prevention of recurrent respiratory infections in children: a multicentre study. Int J Immunopathol Pharmacol 27 (2014) 413-9.
[20] H. Niu, R. Wang, Y.T. Jia, and Y. Cai, Pidotimod, an immunostimulant in pediatric recurrent respiratory tract infections: A meta-analysis of randomized controlled trials. Int Immunopharmacol 67 (2019) 35-45.
[21] S. Manti, F. Filosco, G.F. Parisi, G.G. Finocchiaro, M. Papale, A. Giugno, P. Barone, and S. Leonardi, Proposal for a new therapeutic high dosage of Pidotimod in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: a randomized controlled study. Ital J Pediatr 46 (2020) 106.
[22] S. Esposito, M. Garziano, V. Rainone, D. Trabattoni, M. Biasin, L. Senatore, P. Marchisio, M. Rossi, N. Principi, and M. Clerici, Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia. J Transl Med 13 (2015) 288.
[23] D. Gourgiotis, N.G. Papadopoulos, A. Bossios, P. Zamanis, and P. Saxoni-Papageorgiou, Immune modulator pidotimod decreases the in vitro expression of CD30 in peripheral blood mononuclear cells of atopic asthmatic and normal children. J Asthma 41 (2004) 285-7.
[24] Y.H. Hejian CHEN, Lingling FU., Effect of pidotimod combined with montelukast sodium in the treatment of patients with asthma and its influence on the inflammatory factors and immune function. Chinese Journal of Primary Medicine and Pharmacy 12 (2020) 2885-2889.
[25] J.B. Vargas Correa, S. Espinosa Morales, J.C. Bolanos Ancona, and J.A. Farfan Ale, [Pidotimod in recurring respiratory infection in children with allergic rhinitis, asthma, or both conditions]. Rev Alerg Mex 49 (2002) 27-32.
[26] B.E. Ferrario, S. Garuti, F. Braido, and G.W. Canonica, Pidotimod: the state of art. Clin Mol Allergy 13 (2015) 8.
[27] Y.X. Sun LX, Zhang DJ, Wang Y, Wang YJ, Li CG, Influence of pidotimod on the IL-16, immunoglobulin and T cell subsets in asthmatic children. J Clin Pediatr 29 (2011) 777–779.
[28] S. Carta, M. Silvestri, and G.A. Rossi, Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression. Ital J Pediatr 39 (2013) 29.
[29] G.L. Marseglia, M. Gelardi, P. Santus, and G. Ciprandi, Reappraisal of Pidotimod: an immunomodulatory agent with 30-year evidence. Minerva Med 115 (2024) 503-515.
[30] I.P. Kedia Yash Sanjay, Rathi Vidushi, Pidotimod – Current Role and Evidence. Journal of Advanced Lung Health. 5 (2024) 4-7.
[31] A. Ciaccia, Pidotimod activity against chronic bronchitis exacerbations. Arzneimittelforschung 44 (1994) 1516-20.
[32] G.P. Benetti, M.T. Illeni, A. Passera, G. Bombelli, G. Lavecchia, and C. Uslenghi, Ex vivo evaluation of pidotimod activity in patients with chronic obstructive pulmonary disease. Arzneimittelforschung 44 (1994) 1503-5.
[33] C. Ucciferri, K. Falasca, M. Reale, M. Tamburro, A. Auricchio, F. Vignale, and J. Vecchiet, Pidotimod and Immunological Activation in Individuals Infected with HIV. Curr HIV Res 19 (2021) 260-268.
[34] D. Larenas-Linnemann, N. Rodriguez-Perez, A. Arias-Cruz, M.V. Blandon-Vijil, B.E. Del Rio-Navarro, A. Estrada-Cardona, J.E. Gereda, J.A. Luna-Pech, E.M. Navarrete-Rodriguez, E. Onuma-Takane, C.F. Pozo-Beltran, and M.I. Rojo-Gutierrez, Enhancing innate immunity against virus in times of COVID-19: Trying to untangle facts from fictions. World Allergy Organ J 13 (2020) 100476.
[35] A.N. Chatterjee, and F. Al Basir, A Model for SARS-CoV-2 Infection with Treatment. Comput Math Methods Med 2020 (2020) 1352982.
[36] C. Ucciferri, M. Barone, J. Vecchiet, and K. Falasca, Pidotimod in Paucisymptomatic SARS-CoV2 Infected Patients. Mediterr J Hematol Infect Dis 12 (2020) e2020048.
[37] G.J. Pradyut Waghray, Purva Thatai, Vamsi Krishna Kolukula, Efficacy and Safety of Pidotimod in SARS-CoV-2 Management: A Real-world Evidence Study. International Journal of Clinical Skills 15 (2021) 510-517.
[38] C. Ucciferri, A. Di Gasbarro, P. Borrelli, M. Di Nicola, J. Vecchiet, and K. Falasca, New Therapeutic Options in Mild Moderate COVID-19 Outpatients. Microorganisms 10 (2022).
[39] P. Santus, D. Radovanovic, M. Garziano, S. Pini, G. Croce, G. Fuccia, D. Spitaleri, M. Biasin, M. Clerici, and D. Trabattoni, Anti-Inflammatory Effects of Immunostimulation in Patients with COVID-19 Pneumonia. J Clin Med 10 (2021).
[40] C. Ucciferri, L. Moffa, S. Moffa, J. Vecchiet, and K. Falasca, Are monoclonal antibodies effective in patients with severe obesity in SARS-CoV-2 infected? Immun Inflamm Dis 11 (2023) e771.
[41] C. R., Pidotimod activity in patients affected by COPD. Minerva Pneumol 53 (2014) 21-6.
[42] C. Ucciferri, J. Vecchiet, A. Auricchio, and K. Falasca, Improving BNT162b2 mRNA Vaccine Tolerability without Efficacy Loss by Pidotimod Supplementation. Mediterr J Hematol Infect Dis 14 (2022) e2022023.
[43] N. Zhao, C. Liu, C. Zhu, X. Dong, and X. Liu, Pidotimod: a review of its pharmacological features and clinical effectiveness in respiratory tract infections. Expert Rev Anti Infect Ther 17 (2019) 803-818.
[44] A. Mahashur, A. Vora, P. Waghray, S.Z. Jafrey, A. Karadkhele, S. Muchhala, R. Rathod, and V. Suvarna, Expert Opinion on Usage of Pidotimod in Adult Patients with Chronic Obstructive Pulmonary Disease: An Indian Perspective. J Assoc Physicians India 69 (2021) 11-12.
Article Sidebar
Article Details
How to Cite
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers. Authors will grant copyright of their articles to the Institute of Hematology, Catholic University, Rome . No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.