Pentoxifylline Explained

Pentoxifylline, also known as oxpentifylline, is a xanthine derivative used as a drug to treat muscle pain in people with peripheral artery disease.[1] It is generic and sold under many brand names worldwide.[2]

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. This is its only FDA, MHRA and TGA-labelled indication.[3] [4] 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) [5] as this has been shown to improve healing rates.[6]

Pentoxifylline has been tested for use in sarcoidosis patients as an alternative or compliment to prednisone and other steroids, as the drug can inhibit excess levels of TNF-a, which is associated with granuloma formation.[7] [8] [9] It has further been used to treat immunologic reactions to leprosy with some success.[10] Benefit in alcoholic hepatitis was shown, with some studies demonstrating a reduction in risk of hepatorenal syndrome.For in vitro fertilization, Pentoxifylline has been used to improve sperm quality and motility[11] [12] and as safe oral drug in the treatment of male infertility with erectile dysfunction.[13] [14]

An interesting 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.[15] 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.[16] 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).

The combination of tocopherol and pentoxifylline has been evaluated for the treatment of medication-related osteonecrosis of the jaw.[17]

Pentoxifylline may be used transdermally for cellulite treatment.

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.[3] [4]

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

Mechanism

Like other methylated xanthine derivatives, pentoxifylline is a competitive nonselective phosphodiesterase inhibitor[18] which raises intracellular cAMP, activates PKA, inhibits TNF[19] [20] and leukotriene[21] synthesis, and reduces inflammation and innate immunity.[21] 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.[22] Pentoxifylline is also an antagonist at adenosine 2 receptors.[23]

Research

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.[24] Animal studies have been conducted exploring the use of pentoxifylline for erectile dysfunction[25] and hearing loss.[26] Human studies have been conducted for Peyronie's disease.[27]

Pentoxifylline, in combination with tocopherol and clodronate, has been found to heal refractory osteoradionecrosis of the jaw,[28] and to be prophylactic against osteoradionecrosis.[29]

In a Cochrane systematic review on the use of pentoxifylline for intermittent claudication in 2015, the following was 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".[30]

See also

External links

Notes and References

  1. Broderick C, Forster R, Abdel-Hadi M, Salhiyyah K . Pentoxifylline for intermittent claudication . The Cochrane Database of Systematic Reviews . 2020 . 10 . CD005262 . October 2020 . 33063850 . 8094235 . 10.1002/14651858.CD005262.pub4 .
  2. Drugs.com drugs.com international listings for Pentoxifylline. Page accessed Feb 1, 206
  3. Web site: PENTOXIFYLLINE tablet, extended release [Apotex Corp.]]. DailyMed. Apotex Corp.. February 2013. 3 February 2014.
  4. Web site: Trental 400 - Summary of Product Characteristics (SPC). electronic Medicines Compendium. Sanofi. 10 October 2013. 3 February 2014.
  5. SIGN (2010) Management of chronic venous leg ulcers. Clinical guideline No. 120. Scottish Intercollegiate Guidelines Network. www.sign.ac.uk
  6. Jull AB, Arroll B, Parag V, Waters J . Pentoxifylline for treating venous leg ulcers . The Cochrane Database of Systematic Reviews . 12 . CD001733 . December 2012 . 12 . 23235582 . 7061323 . 10.1002/14651858.CD001733.pub3 .
  7. Zabel P, Entzian P, Dalhoff K, Schlaak M . Pentoxifylline in treatment of sarcoidosis . American Journal of Respiratory and Critical Care Medicine . 155 . 5 . 1665–1669 . May 1997 . 9154873 . 10.1164/ajrccm.155.5.9154873 .
  8. Park MK, Babaali H, Gilbert-McClain LI, Stylianou M, Joo J, Moss J, Manganiello VC . Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis . Sarcoidosis, Vasculitis, and Diffuse Lung Diseases . 26 . 2 . 121–131 . July 2009 . 20560292 . 2946799 .
  9. Tong Z, Dai H, Chen B, Abdoh Z, Guzman J, Costabel U . Inhibition of cytokine release from alveolar macrophages in pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone . Chest . 124 . 4 . 1526–1532 . October 2003 . 14555589 . 10.1378/chest.124.4.1526 .
  10. Legendre DP, Muzny CA, Swiatlo E . Hansen's disease (Leprosy): current and future pharmacotherapy and treatment of disease-related immunologic reactions . Pharmacotherapy . 32 . 1 . 27–37 . January 2012 . 22392826 . 10.1002/PHAR.1009 . 46569413 .
  11. Mahaldashtian M, Khalili MA, Nottola SA, Woodward B, Macchiarelli G, Miglietta S . Does in vitro application of pentoxifylline have beneficial effects in assisted male reproduction? . Andrologia . 53 . 1 . e13722 . February 2021 . 33112447 . 10.1111/and.13722 . free .
  12. Baldini D, Ferri D, Baldini GM, Lot D, Catino A, Vizziello D, Vizziello G . Sperm Selection for ICSI: Do We Have a Winner? . Cells . 10 . 12 . December 2021 . 3566 . 34944074 . 10.3390/cells10123566 . 8700516 . free .
  13. Lu Y, Su H, Zhang J, Wang Y, Li H . Treatment of Poor Sperm Quality and Erectile Dysfunction With Oral Pentoxifylline: A Systematic Review . Frontiers in Pharmacology . 2022 . 12 . 789787 . 35095501 . 10.3389/fphar.2021.789787 . 8790020 . free .
  14. Korenman SG, Viosca SP . Treatment of vasculogenic sexual dysfunction with pentoxifylline . Journal of the American Geriatrics Society . 41 . 4 . 363–366 . April 1993 . 8463520 . 10.1111/j.1532-5415.1993.tb06941.x . 35396795 .
  15. Hosseini F, Mohammadbeigi A, Aghaali M, Borujerdi R, Parham M . 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 . 31741661 . 6856542 . 10.4103/jrms.JRMS_115_18 . free .
  16. Page JC, Chen EY . Management of painful diabetic neuropathy. A treatment algorithm . Journal of the American Podiatric Medical Association . 87 . 8 . 370–379 . August 1997 . 9274092 . 10.7547/87507315-87-8-370 .
  17. de Carvalho EF, Bertotti M, Migliorati CA, Rocha AC . 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 . 10.1016/j.joms.2021.06.036 . 34339622 . 236884968 . 2023-09-04 .
  18. Essayan DM . Cyclic nucleotide phosphodiesterases . The Journal of Allergy and Clinical Immunology . 108 . 5 . 671–680 . November 2001 . 11692087 . 10.1067/mai.2001.119555 . free .
  19. Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R . Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition . Clinics . 63 . 3 . 321–328 . June 2008 . 18568240 . 2664230 . 10.1590/S1807-59322008000300006 .
  20. Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U . Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages . American Journal of Respiratory and Critical Care Medicine . 159 . 2 . 508–511 . February 1999 . 9927365 . 10.1164/ajrccm.159.2.9804085 .
  21. Peters-Golden M, Canetti C, Mancuso P, Coffey MJ . Leukotrienes: underappreciated mediators of innate immune responses . Journal of Immunology . 174 . 2 . 589–594 . January 2005 . 15634873 . 10.4049/jimmunol.174.2.589 . free .
  22. Ward A, Clissold SP . Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy . Drugs . 34 . 1 . 50–97 . July 1987 . 3308412 . 10.2165/00003495-198734010-00003 . 195697501 .
  23. Rodríguez-Morán M, Guerrero-Romero F . Efficacy of pentoxifylline in the management of microalbuminuria in patients with diabetes . Current Diabetes Reviews . 4 . 1 . 55–62 . February 2008 . 18220696 . 10.2174/157339908783502343 .
  24. Li W, Zheng L, Sheng C, Cheng X, Qing L, Qu S . Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease . Lipids in Health and Disease . 10 . 49 . April 2011 . 21477300 . 3088890 . 10.1186/1476-511X-10-49 . free .
  25. Anele UA, Morrison BF, Burnett AL . Molecular pathophysiology of priapism: emerging targets . Current Drug Targets . 16 . 5 . 474–483 . 2015 . 25392014 . 4430197 . 10.2174/1389450115666141111111842 .
  26. Latoni J, Shivapuja B, Seidman MD, Quirk WS . Pentoxifylline maintains cochlear microcirculation and attenuates temporary threshold shifts following acoustic overstimulation . Acta Oto-Laryngologica . 116 . 3 . 388–394 . May 1996 . 8790737 . 10.3109/00016489609137862 .
  27. El-Sakka AI . Reversion of penile fibrosis: Current information and a new horizon . Arab Journal of Urology . 9 . 1 . 49–55 . March 2011 . 26579268 . 4149188 . 10.1016/j.aju.2011.03.013 .
  28. Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL . 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 . 832–9 . July 2011 . 20638190 . 10.1016/j.ijrobp.2010.03.029 . free .
  29. Patel V, Gadiwalla Y, Sassoon I, Sproat C, Kwok J, McGurk M . 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 . 547–50 . June 2016 . 26975577 . 10.1016/j.bjoms.2016.02.024 .
  30. Salhiyyah K, Forster R, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA . Pentoxifylline for intermittent claudication . The Cochrane Database of Systematic Reviews . 9 . 9 . CD005262 . September 2015 . 26417854 . 6513423 . 10.1002/14651858.cd005262.pub3 .

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