Chemistry:Pentoxifylline

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Pentoxifylline, also known as oxpentifylline, is a xanthine derivative used as a drug to treat muscle pain in people with peripheral artery disease.[1][2] It was approved for medical use in 1984 and is available as generic and sold under many brand names worldwide like Trental.[3][4]

Medical uses

Its primary use in medicine is to reduce pain, cramping, numbness, or weakness in the arms or legs which occurs due to intermittent claudication, a form of muscle pain resulting from peripheral artery diseases.[1] This is its only FDA, MHRA and TGA-labelled indication.[5][6][7] However, pentoxifylline is also recommended for off-label use as an adjunct to compression bandaging for the treatment of chronic venous leg ulcers by the Scottish Intercollegiate Guidelines Network (SIGN) [8] as this has been shown to improve healing rates.[9]

Adverse effects

Common side effects are belching, bloating, stomach discomfort or upset, nausea, vomiting, indigestion, dizziness, and flushing. Uncommon and rare side effects include angina, palpitations, hypersensitivity, itchiness, rash, hives, bleeding, hallucinations, arrhythmias, and aseptic meningitis.[5][10][6][7]

Contraindications include intolerance to pentoxifylline or other xanthine derivatives, recent retinal or cerebral haemorrhage, and risk factors for haemorrhage.[10]

Mechanism

Like other methylated xanthine derivatives, pentoxifylline is a competitive nonselective phosphodiesterase inhibitor[11] which raises intracellular cAMP, activates PKA, inhibits TNF[12][13] and leukotriene[14] synthesis, and reduces inflammation and innate immunity.[14] In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and blood clot formation.[15] Pentoxifylline is also an antagonist at adenosine 2 receptors.[16]

Its metabolite lisophillyine is stronger PDE inhibitor than pentoxifylline in vitro.[17]

Research

A 2015 Cochrane systematic review on the use of pentoxifylline for intermittent claudication in 2015 concluded: "The quality of included studies was generally low, and very large variability between studies was noted in reported findings including duration of trials, doses of pentoxifylline and distances participants could walk at the start of trials. Most included studies did not report on randomisation techniques or how treatment allocation was concealed, did not provide adequate information to permit judgement of selective reporting and did not report blinding of outcome assessors. Given all these factors, the role of pentoxifylline in intermittent claudication remains uncertain, although this medication was generally well tolerated by participants".[18][needs update]

Pentoxifylline has been tested for use in sarcoidosis patients as an alternative or complement to prednisone and other steroids, as the drug can inhibit excess levels of TNF-a, which is associated with granuloma formation.[19][20][21]

It has further been used to treat immunologic reactions to leprosy with some success.[22] Benefit in alcoholic hepatitis was shown, with some studies demonstrating a reduction in risk of hepatorenal syndrome. There is some evidence that pentoxifylline can lower the levels of some biomarkers in non-alcoholic steatohepatitis but evidence is insufficient to determine if the drug is safe and effective for this use.[23]

For in vitro fertilization, Pentoxifylline has been used to improve sperm quality and motility[24][25] and as safe oral drug in the treatment of male infertility with erectile dysfunction.[26][27] Animal studies have been conducted exploring the use of pentoxifylline for erectile dysfunction.[28]

An off-label indication of pentoxifylline is the supportive treatment of distal diabetic neuropathy, where it can be added, for example, to thioctic acid or gabapentin.[29] Theoretically, it can (among other things) act prophylactically against ulcerative changes of the lower limbs associated with chronically decompensated diabetes. Patients with measurable impairment in arterial supply are more likely to benefit from adjunctive treatment with pentoxifylline.[30] The administration of higher doses of pentoxifylline in hospitalization for complications of distal diabetic neuropathy is usually conditioned by the joint agreement of the neurologist with the physicians of internal medicine (diabetology and angiology).

Pentoxifylline may be used transdermally for cellulite treatment.[31]

A 2025 systematic review found that pentoxifylline may effectively treat some forms of inner ear vertigo and acute tinnitus, though its impact on idiopathic sudden sensorineural hearing loss remains inconsistent and often suggests ineffectiveness.[32] Animal studies have been conducted exploring the use of pentoxifylline for hearing loss.[33]

Pentoxifylline has been studied and adopted by some clinicians as an oral treatment for Peyronie's disease. It's proposed to act through multiple mechanisms, including antioxidant, antifibrotic (including reducing TGF-β), and anti-inflammatory pathways, to interfere with the disease's pathogenesis and reduce symptoms such as penile curvature, pain, and plaque volume. While systematic reviews indicate a lack of consistent large-scale evidence for its efficacy, various clinical studies and case reports suggest that pentoxifylline, especially in combination with other therapies, may effectively reduce the progression of Peyronie's disease.[34][35]

The combination of tocopherol and pentoxifylline has been evaluated for the treatment of medication-related osteonecrosis of the jaw.[36] Pentoxifylline, in combination with tocopherol and clodronate, has also been found to heal refractory osteoradionecrosis of the jaw,[37] and to be prophylactic against osteoradionecrosis.[38]

Meta-analyses have found that pentoxifylline may be an effective adjunctive treatment for certain cases of major depressive disorder. Clinical studies demonstrated that adding pentoxifylline to standard selective serotonin reuptake inhibitor therapy significantly improved depressive symptom scores on rating scales and increased patient response and remission rates compared to placebo. The drug was associated with improvement in certain forms of cognitive impairment, particularly in vascular dementia.[39][40]

See also

  • Lisofylline, an active metabolite of pentoxifylline
  • Propentofylline
  • Cilostazol, a PDE-3 inhibitor with better evidence for intermittent claudication on the Cochrane review cited above.

References

  1. ↑ 1.0 1.1 "Pentoxifylline for intermittent claudication". The Cochrane Database of Systematic Reviews 2020 (10). October 2020. doi:10.1002/14651858.CD005262.pub4. PMID 33063850. 
  2. ↑ "Pentoxifylline", StatPearls (Treasure Island (FL): StatPearls Publishing), 2025, PMID 32644522, https://www.ncbi.nlm.nih.gov/books/NBK559096/, retrieved 18 June 2025 
  3. ↑ Drugs.com drugs.com international listings for Pentoxifylline. Page accessed 1 February 2016
  4. ↑ "Effects and limitations of pentoxifylline therapy in various stages of peripheral vascular disease of the lower extremity". American Journal of Surgery 160 (3): 266–70. September 1990. doi:10.1016/s0002-9610(06)80020-6. PMID 2393054. 
  5. ↑ 5.0 5.1 Cite error: Invalid <ref> tag; no text was provided for refs named TGA
  6. ↑ 6.0 6.1 "PENTOXIFYLLINE tablet, extended release [Apotex Corp."]. DailyMed. Apotex Corp.. February 2013. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=40ae2d9a-0d95-640d-0640-f76e7e1a13cb#nlm34067-9. 
  7. ↑ 7.0 7.1 "Trental 400 - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Sanofi. 10 October 2013. https://www.medicines.org.uk/emc/medicine/338/SPC/Trental+400/. 
  8. ↑ SIGN (2010) Management of chronic venous leg ulcers. Clinical guideline No. 120. Scottish Intercollegiate Guidelines Network. www.sign.ac.uk ISBN 978-1-905813-66-7
  9. ↑ "Pentoxifylline for treating venous leg ulcers". The Cochrane Database of Systematic Reviews 2012 (12). December 2012. doi:10.1002/14651858.CD001733.pub3. PMID 23235582. 
  10. ↑ 10.0 10.1 Cite error: Invalid <ref> tag; no text was provided for refs named MSR
  11. ↑ "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology 108 (5): 671–680. November 2001. doi:10.1067/mai.2001.119555. PMID 11692087. 
  12. ↑ "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics (Sao Paulo, Brazil) 63 (3): 321–328. June 2008. doi:10.1590/S1807-59322008000300006. PMID 18568240. 
  13. ↑ "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine 159 (2): 508–511. February 1999. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365. 
  14. ↑ 14.0 14.1 "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology (Baltimore, Md.) 174 (2): 589–594. January 2005. doi:10.4049/jimmunol.174.2.589. PMID 15634873. 
  15. ↑ "Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy". Drugs 34 (1): 50–97. July 1987. doi:10.2165/00003495-198734010-00003. PMID 3308412. 
  16. ↑ "Efficacy of pentoxifylline in the management of microalbuminuria in patients with diabetes". Current Diabetes Reviews 4 (1): 55–62. February 2008. doi:10.2174/157339908783502343. PMID 18220696. 
  17. ↑ "PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response". Naunyn-Schmiedeberg's Archives of Pharmacology 390 (10): 1047–1059. 2017. doi:10.1007/s00210-017-1406-z. PMID 28730281. 
  18. ↑ "Pentoxifylline for intermittent claudication". The Cochrane Database of Systematic Reviews 9 (9). September 2015. doi:10.1002/14651858.cd005262.pub3. PMID 26417854. 
  19. ↑ "Pentoxifylline in treatment of sarcoidosis". American Journal of Respiratory and Critical Care Medicine 155 (5): 1665–1669. May 1997. doi:10.1164/ajrccm.155.5.9154873. PMID 9154873. 
  20. ↑ "Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis". Sarcoidosis, Vasculitis, and Diffuse Lung Diseases 26 (2): 121–131. July 2009. PMID 20560292. 
  21. ↑ "Inhibition of cytokine release from alveolar macrophages in pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone". Chest 124 (4): 1526–1532. October 2003. doi:10.1378/chest.124.4.1526. PMID 14555589. 
  22. ↑ "Hansen's disease (Leprosy): current and future pharmacotherapy and treatment of disease-related immunologic reactions". Pharmacotherapy 32 (1): 27–37. January 2012. doi:10.1002/PHAR.1009. PMID 22392826. 
  23. ↑ "Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease". Lipids in Health and Disease 10. April 2011. doi:10.1186/1476-511X-10-49. PMID 21477300. 
  24. ↑ "Does in vitro application of pentoxifylline have beneficial effects in assisted male reproduction?". Andrologia 53 (1). February 2021. doi:10.1111/and.13722. PMID 33112447. 
  25. ↑ "Sperm Selection for ICSI: Do We Have a Winner?". Cells 10 (12): 3566. December 2021. doi:10.3390/cells10123566. PMID 34944074. 
  26. ↑ "Treatment of Poor Sperm Quality and Erectile Dysfunction With Oral Pentoxifylline: A Systematic Review". Frontiers in Pharmacology 12. 2022. doi:10.3389/fphar.2021.789787. PMID 35095501.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  27. ↑ "Treatment of vasculogenic sexual dysfunction with pentoxifylline". Journal of the American Geriatrics Society 41 (4): 363–366. April 1993. doi:10.1111/j.1532-5415.1993.tb06941.x. PMID 8463520. 
  28. ↑ "Molecular pathophysiology of priapism: emerging targets". Current Drug Targets 16 (5): 474–483. 2015. doi:10.2174/1389450115666141111111842. PMID 25392014. 
  29. ↑ "Effect of pentoxifylline on diabetic distal polyneuropathy in type 2 diabetic patients: A randomized trial". Journal of Research in Medical Sciences 24 (1): 89. 2019. doi:10.4103/jrms.JRMS_115_18. PMID 31741661. 
  30. ↑ "Management of painful diabetic neuropathy. A treatment algorithm". Journal of the American Podiatric Medical Association 87 (8): 370–379. August 1997. doi:10.7547/87507315-87-8-370. PMID 9274092. 
  31. ↑ "Cosmeceuticals for cellulite". Seminars in Cutaneous Medicine and Surgery 30 (3): 167–70. September 2011. doi:10.1016/j.sder.2011.06.005. PMID 21925371. 
  32. ↑ "Pentoxifylline uses in inner ear diseases". European Journal of Clinical Pharmacology 81 (7): 955–999. July 2025. doi:10.1007/s00228-025-03844-4. PMID 40332573. 
  33. ↑ "Pentoxifylline maintains cochlear microcirculation and attenuates temporary threshold shifts following acoustic overstimulation". Acta Oto-Laryngologica 116 (3): 388–394. May 1996. doi:10.3109/00016489609137862. PMID 8790737. 
  34. ↑ "Oxidative Mechanism of Peyronie's Disease and Effectiveness of Pentoxifylline in the Therapeutic Management: A Narrative Review". Antioxidants 14 (2). February 2025. doi:10.3390/antiox14020208. PMID 40002394. 
  35. ↑ "Reversion of penile fibrosis: Current information and a new horizon". Arab Journal of Urology 9 (1): 49–55. March 2011. doi:10.1016/j.aju.2011.03.013. PMID 26579268. 
  36. ↑ "Cilostazol and Tocopherol in the Management of Medication-Related Osteonecrosis of the Jaw: New Insights From a Case Report". Journal of Oral and Maxillofacial Surgery 79 (12): 2499–2506. December 2021. doi:10.1016/j.joms.2021.06.036. PMID 34339622. https://www.practiceupdate.com/content/adjunctive-effect-of-pentoxifylline-and-tocopherol-in-the-management-of-medication-related-osteonecrosis-of-the-jaw/155064. Retrieved 4 September 2023. 
  37. ↑ "Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial". International Journal of Radiation Oncology, Biology, Physics 80 (3): 832–839. July 2011. doi:10.1016/j.ijrobp.2010.03.029. PMID 20638190. 
  38. ↑ "Prophylactic use of pentoxifylline and tocopherol in patients who require dental extractions after radiotherapy for cancer of the head and neck". The British Journal of Oral & Maxillofacial Surgery 54 (5): 547–550. June 2016. doi:10.1016/j.bjoms.2016.02.024. PMID 26975577. 
  39. ↑ "Effects of the anti-inflammatory pentoxifylline on psychiatric and neuropsychiatric conditions: exploring various off-label utilities with meta-analyses". Inflammopharmacology 33 (1): 105–119. January 2025. doi:10.1007/s10787-024-01616-7. PMID 39775244. 
  40. ↑ "Efficacy, safety and mechanistic insights of pentoxifylline in major depressive disorder: a systematic review and meta-analysis of randomized controlled trials". Naunyn-Schmiedeberg's Archives of Pharmacology 398 (7): 8125–8138. July 2025. doi:10.1007/s00210-025-03845-1. PMID 39985579. 



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