BACKGROUND AND OBJECTIVE: Theophylline has been used for decades in human medicine for its psychostimulant, anti-inflammatory, and bronchodilator effects. Historically, in pulmonary medicine, theophylline has been used in the treatment of obstructive pulmonary diseases such as bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD). This review aims to determine whether theophylline still has its place in the therapy of obstructive pulmonary diseases or whether we can even extend its use to other diagnoses such as atropine-resistant cardiac arrests, apnea of prematurity, or others. Moreover, we also aim to determine if there is a rationale for using low-dose theophylline due to its immunomodulatory and anti-inflammatory effect, or if the future of methylxanthines lies in newly synthesized derivates of theophylline such as bamifylline, or doxofylline. METHODS: The narrative review is based on a literature search of the articles indexed in the PubMed database in 2023. We searched the database since the year 2009 using the MeSH terms "theophylline", "aminophylline", and "methylxanthines" and we included original articles in the English language. KEY CONTENT AND FINDINGS: Theophylline has a number of adverse drug reactions (ADRs), the most serious of which is its effect on the cardiovascular system. It can cause severe arrhythmias or even cardiac arrest when overdosed. On the other hand, there is still a substantial amount of its applications in current clinical practice. CONCLUSIONS: There is considerable controversy associated with its use in current medicine, which can be attributed both to its narrow therapeutic range and its mentioned cardiotoxic effect. Herein, we summarize the current state-of-art of theophylline and its use in human medicine.

Department of Respiratory Diseases University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

International Clinical Research Center St Anne's University Hospital Brno Czechia

Zobrazit více v PubMed

Franco R, Oñatibia-Astibia A, Martínez-Pinilla E. Health benefits of methylxanthines in cacao and chocolate. Nutrients 2013;5:4159-73. 10.3390/nu5104159 PubMed DOI PMC

Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 2001;108:671-80. 10.1067/mai.2001.119555 PubMed DOI

Page CP, Barnes PJ. Pharmacology and Therapeutics of Asthma and COPD. Cham: Springer; 2017.

Maurice DH, Ke H, Ahmad F, et al. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 2014;13:290-314. 10.1038/nrd4228 PubMed DOI PMC

Varani K, Caramori G, Vincenzi F, et al. Alteration of adenosine receptors in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:398-406. 10.1164/rccm.200506-869OC PubMed DOI

Brown RA, Clarke GW, Ledbetter CL, et al. Elevated expression of adenosine A1 receptor in bronchial biopsy specimens from asthmatic subjects. Eur Respir J 2008;31:311-9. 10.1183/09031936.00003707 PubMed DOI

Polosa R, Blackburn MR. Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease. Trends Pharmacol Sci 2009;30:528-35. 10.1016/j.tips.2009.07.005 PubMed DOI PMC

Cushley MJ, Tattersfield AE, Holgate ST. Adenosine-induced bronchoconstriction in asthma. Antagonism by inhaled theophylline. Am Rev Respir Dis 1984;129:380-4. 10.1164/arrd.1984.129.3.380 PubMed DOI

Cushley MJ, Holgate ST. Adenosine-induced bronchoconstriction in asthma: role of mast cell-mediator release. J Allergy Clin Immunol 1985;75:272-8. 10.1016/0091-6749(85)90057-0 PubMed DOI

Mann JS, Holgate ST. Specific antagonism of adenosine-induced bronchoconstriction in asthma by oral theophylline. Br J Clin Pharmacol 1985;19:685-92. 10.1111/j.1365-2125.1985.tb02696.x PubMed DOI PMC

Stein MA, Krasowski M, Leventhal BL, et al. Behavioral and cognitive effects of methylxanthines. A meta-analysis of theophylline and caffeine. Arch Pediatr Adolesc Med 1996;150:284-8. 10.1001/archpedi.1996.02170280054010 PubMed DOI

Rappaport L, Coffman H, Guare R, et al. Effects of theophylline on behavior and learning in children with asthma. Am J Dis Child 1989;143:368-72. 10.1001/archpedi.1989.02150150126032 PubMed DOI

Barnes PJ. Theophylline. Am J Respir Crit Care Med 2013;188:901-6. 10.1164/rccm.201302-0388PP PubMed DOI

To Y, Ito K, Kizawa Y, et al. Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;182:897-904. 10.1164/rccm.200906-0937OC PubMed DOI PMC

Hendeles L, Massanari M, Weinberger M. Update on the pharmacodynamics and pharmacokinetics of theophylline. Chest 1985;88:103S-11S. 10.1378/chest.88.2_supplement.103s PubMed DOI

Molfino NA, Zhang P. A meta-analysis on the efficacy of oral theophylline in patients with stable COPD. Int J Chron Obstruct Pulmon Dis 2006;1:261-6. 10.2147/copd.2006.1.3.261 PubMed DOI PMC

Fink G, Kaye C, Sulkes J, et al. Effect of theophylline on exercise performance in patients with severe chronic obstructive pulmonary disease. Thorax 1994;49:332-4. 10.1136/thx.49.4.332 PubMed DOI PMC

Chrystyn H, Mulley BA, Peake MD. Dose response relation to oral theophylline in severe chronic obstructive airways disease. BMJ 1988;297:1506-10. 10.1136/bmj.297.6662.1506 PubMed DOI PMC

Ram FS. Use of theophylline in chronic obstructive pulmonary disease: examining the evidence. Curr Opin Pulm Med 2006;12:132-9. 10.1097/01.mcp.0000208453.95972.e2 PubMed DOI

Yokoba M, Katagiri M, Ichikawa T, et al. Aminophylline increases respiratory muscle activity during hypercapnia in humans. Pulm Pharmacol Ther 2015;30:96-101. 10.1016/j.pupt.2014.03.006 PubMed DOI

Jagers JV, Hawes HG, Easton PA. Aminophylline increases ventilation and diaphragm contractility in awake canines. Respir Physiol Neurobiol 2009;167:273-80. 10.1016/j.resp.2009.05.008 PubMed DOI

Mitenko PA, Ogilvie RI. Rational intravenous doses of theophylline. N Engl J Med 1973;289:600-3. 10.1056/NEJM197309202891202 PubMed DOI

Murciano D, Aubier M, Lecocguic Y, et al. Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 1984;311:349-53. 10.1056/NEJM198408093110601 PubMed DOI

Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokinet 1978;3:267-93. 10.2165/00003088-197803040-00002 PubMed DOI

Nantwi KD, El-Bohy A, Goshgarian HG. Actions of systemic theophylline on hemidiaphragmatic recovery in rats following cervical spinal cord hemisection. Exp Neurol 1996;140:53-9. 10.1006/exnr.1996.0114 PubMed DOI

Lim S, Tomita K, Caramori G, et al. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001;164:273-6. 10.1164/ajrccm.164.2.2006043 PubMed DOI

Kanehara M, Yokoyama A, Tomoda Y, et al. Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2008;21:874-8. 10.1016/j.pupt.2008.09.003 PubMed DOI

Baba K, Sakakibara A, Yagi T, et al. Effects of theophylline withdrawal in well-controlled asthmatics treated with inhaled corticosteroid. J Asthma 2001;38:615-24. 10.1081/jas-100107539 PubMed DOI

Minoguchi K, Kohno Y, Oda N, et al. Effect of theophylline withdrawal on airway inflammation in asthma. Clin Exp Allergy 1998;28 Suppl 3:57-63. PubMed

Bresnick E, Woodard WK, Sageman CB. Fatal reactions to intravenous administration of aminophylline; report of three cases. J Am Med Assoc 1948;136:397. 10.1001/jama.1948.72890230007008 PubMed DOI

Olson KR, Benowitz NL, Woo OF, et al. Theophylline overdose: acute single ingestion versus chronic repeated overmedication. Am J Emerg Med 1985;3:386-94. 10.1016/0735-6757(85)90195-0 PubMed DOI

Kong A, Ghosh S, Guan C, et al. Acute on Chronic Theophylline Toxicity in an Elderly Patient. Cureus 2021;13:e13484. 10.7759/cureus.13484 PubMed DOI PMC

Bittar G, Friedman HS. The arrhythmogenicity of theophylline. A multivariate analysis of clinical determinants. Chest 1991;99:1415-20. 10.1378/chest.99.6.1415 PubMed DOI

Levine JH, Michael JR, Guarnieri T. Multifocal atrial tachycardia: a toxic effect of theophylline. Lancet 1985;1:12-4. 10.1016/s0140-6736(85)90964-x PubMed DOI

Shannon M. Life-threatening events after theophylline overdose: a 10-year prospective analysis. Arch Intern Med 1999;159:989-94. 10.1001/archinte.159.9.989 PubMed DOI

Sessler CN, Cohen MD. Cardiac arrhythmias during theophylline toxicity. A prospective continuous electrocardiographic study. Chest 1990;98:672-8. 10.1378/chest.98.3.672 PubMed DOI

Varriale P, Ramaprasad S. Aminophylline induced atrial fibrillation. Pacing Clin Electrophysiol 1993;16:1953-5. 10.1111/j.1540-8159.1993.tb00987.x PubMed DOI

Suissa S, Hemmelgarn B, Blais L, et al. Bronchodilators and acute cardiac death. Am J Respir Crit Care Med 1996;154:1598-602. 10.1164/ajrccm.154.6.8970341 PubMed DOI

Lee TA, Schumock GT, Bartle B, et al. Mortality risk in patients receiving drug regimens with theophylline for chronic obstructive pulmonary disease. Pharmacotherapy 2009;29:1039-53. 10.1592/phco.29.9.1039 PubMed DOI

Turan A, Kasuya Y, Govinda R, et al. The effect of aminophylline on loss of consciousness, bispectral index, propofol requirement, and minimum alveolar concentration of desflurane in volunteers. Anesth Analg 2010;110:449-54. 10.1213/ANE.0b013e3181c6be7e PubMed DOI

Stirt JA. Aminophylline may act as a morphine antagonist. Anaesthesia 1983;38:275-8. 10.1111/j.1365-2044.1983.tb13990.x PubMed DOI

Krintel JJ, Wegmann F. Aminophylline reduces the depth and duration of sedation with barbiturates. Acta Anaesthesiol Scand 1987;31:352-4. 10.1111/j.1399-6576.1987.tb02582.x PubMed DOI

Meyer BH, Weis OF, Müller FO. Antagonism of diazepam by aminophylline in healthy volunteers. Anesth Analg 1984;63:900-2. PubMed

Minton NA, Henry JA. Treatment of theophylline overdose. Am J Emerg Med 1996;14:606-12. 10.1016/S0735-6757(96)90111-4 PubMed DOI

Rogliani P, Ora J, Puxeddu E, et al. Adherence to COPD treatment: Myth and reality. Respir Med 2017;129:117-23. 10.1016/j.rmed.2017.06.007 PubMed DOI

Ma YJ, Jiang DQ, Meng JX, et al. Theophylline: a review of population pharmacokinetic analyses. J Clin Pharm Ther 2016;41:594-601. 10.1111/jcpt.12435 PubMed DOI

Karamchand S, Williams M, Naidoo P, et al. Post-tuberculous lung disease: should we be using Theophylline? J Thorac Dis 2021;13:1230-8. 10.21037/jtd-20-1298 PubMed DOI PMC

Global Initiative for Chronic Obstructive Lung Disease. Global strategy for prevention, diagnosis and management of COPD: 2024 report. Available online: https://goldcopd.org/2024-gold-report/

Nici L, Mammen MJ, Charbek E, et al. Pharmacologic Management of Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2020;201:e56-e69. Erratum in: Am J Respir Crit Care Med 2020;202:910.10.1164/rccm.202003-0625ST PubMed DOI PMC

Miravitlles M, Vogelmeier C, Roche N, et al. A review of national guidelines for management of COPD in Europe. Eur Respir J 2016;47:625-37. 10.1183/13993003.01170-2015 PubMed DOI PMC

Zysman M, Chabot F, Housset B, et al. Pharmacological treatment optimisation for stable COPD: an endless story? Proposals from the Société de Pneumologie de Langue Française. Eur Respir J 2017;50:1701250. 10.1183/13993003.01250-2017 PubMed DOI

Zatloukal J, Brat K, Neumannova K, et al. Chronic obstructive pulmonary disease - diagnosis and management of stable disease; a personalized approach to care, using the treatable traits concept based on clinical phenotypes. Position paper of the Czech Pneumological and Phthisiological Society. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2020;164:325-56. 10.5507/bp.2020.056 PubMed DOI

Lee JK, Rhee CK, Kim K, et al. Prescription Status and Clinical Outcomes of Methylxanthines and Leukotriene Receptor Antagonists in Mild-to-Moderate Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis 2019;14:2639-47. 10.2147/COPD.S216326 PubMed DOI PMC

Shih YN, Chen YT, Chu H, et al. Association of pre-hospital theophylline use and mortality in chronic obstructive pulmonary disease patients with sepsis. Respir Med 2017;125:33-8. 10.1016/j.rmed.2017.02.020 PubMed DOI

Kirsten DK, Wegner RE, Jörres RA, et al. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993;104:1101-7. 10.1378/chest.104.4.1101 PubMed DOI

Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology 2006;11:603-10. 10.1111/j.1440-1843.2006.00897.x PubMed DOI

Rossi A, Kristufek P, Levine BE, et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest 2002;121:1058-69. 10.1378/chest.121.4.1058 PubMed DOI

Horita N, Miyazawa N, Kojima R, et al. Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis. Arch Bronconeumol 2016;52:233-8. 10.1016/j.arbres.2015.02.021 PubMed DOI

Calverley PM, Walker P. Chronic obstructive pulmonary disease. Lancet 2003;362:1053-61. 10.1016/s0140-6736(03)14416-9 PubMed DOI

Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256-76. 10.1164/ajrccm.163.5.2101039 PubMed DOI

Wedzicha JA Ers Co-Chair , Miravitlles M, Hurst JR, et al. Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J 2017;49:1600791. 10.1183/13993003.00791-2016 PubMed DOI

Barr RG, Rowe BH, Camargo CA. Methylxanthines for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2003;(2):CD002168. 10.1002/14651858.CD002168 PubMed DOI

Duffy N, Walker P, Diamantea F, et al. Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Thorax 2005;60:713-7. 10.1136/thx.2004.036046 PubMed DOI PMC

Global Initiative for Asthma. Global Strategy for Asthma Management, and Prevention. 2023. Available online: https://ginasthma.org/

Cazzola M, Matera MG. The effect of doxofylline in asthma and COPD. Respir Med 2020;164:105904. 10.1016/j.rmed.2020.105904 PubMed DOI

Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J 2020;55:1900588. 10.1183/13993003.00588-2019 PubMed DOI

Rivington RN, Boulet LP, Côté J, et al. Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 1995;151:325-32. 10.1164/ajrccm.151.2.7842186 PubMed DOI

Dennis RJ, Solarte I, Rodrigo G. Asthma in adults. BMJ Clin Evid 2011;2011:1512. PubMed PMC

Tee AK, Koh MS, Gibson PG, et al. Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2007;2007:CD001281. 10.1002/14651858.CD001281.pub2 PubMed DOI PMC

Dalabih AR, Bondi SA, Harris ZL, et al. Aminophylline infusion for status asthmaticus in the pediatric critical care unit setting is independently associated with increased length of stay and time for symptom improvement. Pulm Pharmacol Ther 2014;27:57-61. 10.1016/j.pupt.2013.03.001 PubMed DOI PMC

Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled beta(2)-agonists in adults with acute asthma. Cochrane Database Syst Rev 2012;12:CD002742. 10.1002/14651858.CD002742.pub2 PubMed DOI PMC

Mitra A, Bassler D, Goodman K, et al. Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev 2005;2005:CD001276. 10.1002/14651858.CD001276.pub2 PubMed DOI PMC

Cosio BG, Iglesias A, Rios A, et al. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax 2009;64:424-9. 10.1136/thx.2008.103432 PubMed DOI

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;57:2003338. 10.1183/13993003.03338-2020 PubMed DOI

Wieshammer S, Dreyhaupt J, Basler B. Theophylline and cardiac stress in patients with dyspnea: an observational study. Pharmacology 2010;86:189-95. 10.1159/000318853 PubMed DOI

Nie H, Zhang G, Liu M, et al. Efficacy of theophylline plus salmeterol/fluticasone propionate combination therapy in patients with asthma. Respir Med 2013;107:347-54. 10.1016/j.rmed.2012.12.004 PubMed DOI

Ukena D, Schudt C, Sybrecht GW. Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes. Biochem Pharmacol 1993;45:847-51. 10.1016/0006-2952(93)90168-v PubMed DOI

Kidney J, Dominguez M, Taylor PM, et al. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995;151:1907-14. 10.1164/ajrccm.151.6.7767539 PubMed DOI

Eid NS, O'Hagan A, Bickel S, et al. Anti-inflammatory dosing of theophylline in the treatment of status asthmaticus in children. J Asthma Allergy 2016;9:183-9. 10.2147/JAA.S113747 PubMed DOI PMC

Mader TJ, Smithline HA, Durkin L, et al. A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Acad Emerg Med 2003;10:192-7. 10.1111/j.1553-2712.2003.tb01989.x PubMed DOI

Hurley KF, Magee K, Green R. Aminophylline for bradyasystolic cardiac arrest in adults. Cochrane Database Syst Rev 2015;2015:CD006781. 10.1002/14651858.CD006781.pub3 PubMed DOI PMC

Pasnoori VR, Leesar MA. Use of aminophylline in the treatment of severe symptomatic bradycardia resistant to atropine. Cardiol Rev 2004;12:65-8. 10.1097/01.crd.0000096418.72821.fa PubMed DOI

Bertolet BD, McMurtrie EB, Hill JA, et al. Theophylline for the treatment of atrioventricular block after myocardial infarction. Ann Intern Med 1995;123:509-11. 10.7326/0003-4819-123-7-199510010-00006 PubMed DOI

Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS Guideline on the Evaluation and Management of Patients With Bradycardia and Cardiac Conduction Delay: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 2019;74:932-987. Erratum in: J Am Coll Cardiol 2019;74:1014-6.10.1016/j.jacc.2018.10.043 PubMed DOI

Oñatibia-Astibia A, Martínez-Pinilla E, Franco R. The potential of methylxanthine-based therapies in pediatric respiratory tract diseases. Respir Med 2016;112:1-9. 10.1016/j.rmed.2016.01.022 PubMed DOI

Bhatt GC, Gogia P, Bitzan M, et al. Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: a systematic review. Arch Dis Child 2019;104:670-9. 10.1136/archdischild-2018-315805 PubMed DOI

Kim WY, Lim CM. Ventilator-Induced Diaphragmatic Dysfunction: Diagnosis and Role of Pharmacological Agents. Respir Care 2017;62:1485-91. 10.4187/respcare.05622 PubMed DOI

Caruso MK, Pekarovic S, Raum WJ, et al. Topical fat reduction from the waist. Diabetes Obes Metab 2007;9:300-3. 10.1111/j.1463-1326.2006.00600.x PubMed DOI

Fischer R, Lang SM, Steiner U, et al. Theophylline improves acute mountain sickness. Eur Respir J 2000;15:123-7. 10.1183/09031936.00.15112300 PubMed DOI

Basu S, Mitra Basu R. Theophylline as a therapy for chronic lymphocytic leukemia: a case report and review of literature. Haematologia (Budap) 2000;30:225-7. 10.1163/156855900300109242 PubMed DOI

Sharpe A, Bhandari H, Miller D. Is there a role for phosphodiesterase inhibitors in the treatment of male subfertility? Hum Fertil (Camb) 2022;25:13-23. 10.1080/14647273.2020.1793420 PubMed DOI

Page C, Cazzola M. Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease. Eur Respir J 2014;44:475-82. 10.1183/09031936.00003814 PubMed DOI

Riffo-Vasquez Y, Venkatasamy R, Page CP. Steroid sparing effects of doxofylline. Pulm Pharmacol Ther 2018;48:1-4. 10.1016/j.pupt.2017.10.008 PubMed DOI

Zhang Y, Zeng K, Wang J, et al. Identifying the antiasthmatic target of doxofylline using immobilized β2 -adrenoceptor based high-performance affinity chromatography and site-directed molecular docking. J Mol Recognit 2016;29:492-8. 10.1002/jmr.2549 PubMed DOI

van Mastbergen J, Jolas T, Allegra L, et al. The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism. Pulm Pharmacol Ther 2012;25:55-61. 10.1016/j.pupt.2011.10.007 PubMed DOI

Matera MG, Page C, Cazzola M. Doxofylline is not just another theophylline! Int J Chron Obstruct Pulmon Dis 2017;12:3487-93. PubMed PMC

Page CP. Doxofylline: a "novofylline". Pulm Pharmacol Ther 2010;23:231-4. 10.1016/j.pupt.2010.04.002 PubMed DOI

Shukla D, Chakraborty S, Singh S, et al. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin Pharmacother 2009;10:2343-56. 10.1517/14656560903200667 PubMed DOI

Cazzola M, Calzetta L, Barnes PJ, et al. Efficacy and safety profile of xanthines in COPD: a network meta-analysis. Eur Respir Rev 2018;27:180010. 10.1183/16000617.0010-2018 PubMed DOI PMC