Theophylline Revisited. Mechanisms, Challenges, and New Horizons
DOI:
https://doi.org/10.12775/QS.2025.37.57009Keywords
Theophylline, Asthma, COPD, adenosine antagonist, immunomodulation, mitochondria, COVID-19, anti-inflammatoryAbstract
Introduction and Purpose
Theophylline, used for over a century in asthma and COPD treatment, provides anti-inflammatory and bronchodilatory effects via phosphodiesterase inhibition and adenosine receptor antagonism. This review examines its mechanisms, clinical uses, and emerging applications.
Materials and Methods
A detailed analysis of 23 peer-reviewed studies from scientific databases, including PubMed, focused on theophylline’s pharmacokinetics, pharmacodynamics, clinical safety, and novel applications in areas such as immunomodulation, metabolic disorders, and regenerative medicine.
Results
Theophylline shows anti-inflammatory effects, mitochondrial support, and modulation of key pathways (e.g., PI3K/Akt, NF-κB). It demonstrates potential in COVID-19-related ARDS, promoting muscle regeneration, and treating infertility. However, its narrow therapeutic index and variability in pharmacokinetics remain significant challenges.
Conclusion
Theophylline remains a cost-effective option in asthma and COPD and shows promise in broader applications like immunomodulation and metabolic disorders. Further research and advanced drug formulations are needed to enhance its safety and therapeutic potential.
References
Bradbury T, Di Tanna GL, Scaria A, et al. Blood Eosinophils in Chinese COPD Participants and Response to Treatment with Combination Low-Dose Theophylline and Prednisone: A Post-Hoc Analysis of the TASCS Trial. Int J Chron Obstruct Pulmon Dis. 2022;17:273-282. Published 2022 Feb 5. doi:10.2147/COPD.S339889
Purkiewicz A, Pietrzak-Fiećko R, Sörgel F, Kinzig M. Caffeine, Paraxanthine, Theophylline, and Theobromine Content in Human Milk. Nutrients. 2022;14(11):2196. Published 2022 May 25. doi:10.3390/nu14112196
Subudhi AW, Evero O, Reitinger J, et al. Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia. Exp Physiol. 2021;106(1):117-125. doi:10.1113/EP088461
Okada A, Sera S, Taguchi M, Yamada H, Nagai N. Current status and usefulness of therapeutic drug monitoring implementation of theophylline in elderly patients based on a nationwide database study and modeling approach. Sci Prog. 2024;107(3):368504241285122. doi:10.1177/00368504241285122
Kurata Y, Muraki S, Hirota T, Araki H, Ieiri I. Effect of liver cirrhosis on theophylline trough concentrations: A comparative analysis of organ impairment using Child-Pugh and MELD scores. Br J Clin Pharmacol. 2022;88(8):3819-3828. doi:10.1111/bcp.15333
Siddharthan T, Pollard SL, Jackson P, et al. Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial. Trials. 2021;22(1):213. Published 2021 Mar 16. doi:10.1186/s13063-021-05163-2
Tänzler D, Kipping M, Lederer M, et al. Effects of theophylline on ADCY5 activation-From cellular studies to improved therapeutic options for ADCY5-related dyskinesia patients. PLoS One. 2023;18(3):e0282593. Published 2023 Mar 3. doi:10.1371/journal.pone.0282593
Shuai T, Zhang C, Zhang M, et al. Low-dose theophylline in addition to ICS therapy in COPD patients: A systematic review and meta-analysis. PLoS One. 2021;16(5):e0251348. Published 2021 May 24. doi:10.1371/journal.pone.0251348
Esmeryan KD, Rangelov I, Chaushev TA. Manipulated sperm motility via soot nanoparticles-induced biochemical alterations in human seminal plasma. Reprod Biol. 2023;23(3):100793. doi:10.1016/j.repbio.2023.100793
Wall GC, Smith HL, Trump MW, et al. Pentoxifylline or theophylline use in hospitalized COVID-19 patients requiring oxygen support. Clin Respir J. 2021;15(7):843-846. doi:10.1111/crj.13363
Modrau B, Winder A, Hjort N, et al. Perfusion Changes in Acute Stroke Treated with Theophylline as an Add-on to Thrombolysis : A Randomized Clinical Trial Subgroup Analysis. Clin Neuroradiol. 2022;32(2):345-352. doi:10.1007/s00062-021-01029-x
Jin IT, Yoon N, Jeong HK, Lee KH, Park HW, Cho JG. Positive chronotropic effects of theophylline and cilostazol in patients with symptomatic sick sinus syndrome who have declined permanent pacing. Rev Cardiovasc Med. 2020;21(3):473-480. doi:10.31083/j.rcm.2020.03.22
Barati-Boldaji R, Shojaei-Zarghani S, Mehrabi M, Amini A, Safarpour AR. Post-dural puncture headache prevention and treatment with aminophylline or theophylline: a systematic review and meta-analysis. Anesth Pain Med (Seoul). 2023;18(2):177-189. doi:10.17085/apm.22247
Karim F, Chang P, Garrison C, Steiner M. Role of Theophylline in Management of Bradycardia Secondary to High Cervical Spinal Cord Injury in a Seven-Year-Old Child: Case Report and a Review of Literature. Cureus. 2020;12(10):e10941. Published 2020 Oct 14. doi:10.7759/cureus.10941
Lee JJ, Peterson AM, Kallogjeri D, et al. Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction. Am J Otolaryngol. 2022;43(2):103299. doi:10.1016/j.amjoto.2021.103299
Oxley-Oxland JV, Freercks R, Baker D, Van der Merwe E. The characteristics and costs of severe theophylline toxicity in a tertiary critical care unit in Eastern Cape Province, South Africa. S Afr Med J. 2022;112(11):866-870. Published 2022 Nov 1. doi:10.7196/SAMJ.2022.v112i11.16453
Jenkins CR, Wen FQ, Martin A, et al. The effect of low-dose corticosteroids and theophylline on the risk of acute exacerbations of COPD: the TASCS randomised controlled trial. Eur Respir J. 2021;57(6):2003338. Published 2021 Jun 10. doi:10.1183/13993003.03338-2020
Zhang W, Gao L, Zhang X, et al. Theophylline derivatives promote primordial follicle activation via cAMP-PI3K/Akt pathway and ameliorate fertility deficits in naturally aged mice. Int J Biol Sci. 2024;20(13):5312-5329. Published 2024 Sep 30. doi:10.7150/ijbs.99936
Frymoyer A, Van Meurs KP, Drover DR, Klawitter J, Christians U, Chock VY. Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. Pediatr Res. 2020;88(6):871-877. doi:10.1038/s41390-020-01140-8
Liu TT, Liu XT, Huang GL, Liu L, Chen QX, Wang Q. Theophylline Extracted from Fu Brick Tea Affects the Metabolism of Preadipocytes and Body Fat in Mice as a Pancreatic Lipase Inhibitor. Int J Mol Sci. 2022;23(5):2525. Published 2022 Feb 25. doi:10.3390/ijms23052525
Sanmartin-Fernandez M, Zamorano JL. Theophylline for Attenuating Ticagrelor-Related Dyspnea. Teofilina para o Alívio da Dispneia Relacionada ao Ticagrelor. Arq Bras Cardiol. 2021;117(1):146-148. doi:10.36660/abc.20201076
Montaño LM, Sommer B, Gomez-Verjan JC, et al. Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies. Int J Mol Sci. 2022;23(8):4167. Published 2022 Apr 9. doi:10.3390/ijms23084167
Yoshioka Y, Imi Y, Kawabata K, Shibata K, Terao J, Miyoshi N. Theophylline Prevents Dexamethasone-Induced Atrophy in C2C12 Myotubes. J Nutr Sci Vitaminol (Tokyo). 2023;69(4):284-291. doi:10.3177/jnsv.69.284
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Copyright (c) 2025 Jakub Szarłowicz, Michał Mazur, Dorota Waz, Zofia Goliszek, Karolina Łucja Sobek, Wiktoria Tabin-Barczak, Aldona Sokołowska, Klaudia Fikas, Kamil Chwaliszewski, Sebastian Samuła
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