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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
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<!--Clinical data-->
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| pronounce = {{IPAc-en|ˌ|p|ɛ|n|t|ɒ|k|ˈ|s|ɪ|f|ᵻ|l|iː|n|,_|-|ɪ|n}}
| pronounce = {{IPAc-en|ˌ|p|ɛ|n|t|ɒ|k|ˈ|s|ɪ|f|ᵻ|l|iː|n|,_|-|ɪ|n}}
| tradename = Many names worldwide<ref name=generics/>
| tradename = Trental, many other names worldwide<ref name=generics/>
| Drugs.com = {{drugs.com|monograph|pentoxifylline}}
| Drugs.com = {{drugs.com|monograph|pentoxifylline}}
| MedlinePlus = a685027
| MedlinePlus = a685027
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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]].<ref name=":0">{{Cite journal|last=Broderick|first=Cathryn|last2=Forster|first2=Rachel|last3=Abdel-Hadi|first3=Mohammed|last4=Salhiyyah|first4=Kareem|date=October 16, 2020|title=Pentoxifylline for intermittent claudication|url=https://pubmed.ncbi.nlm.nih.gov/33063850|journal=The Cochrane Database of Systematic Reviews|volume=10|pages=CD005262|doi=10.1002/14651858.CD005262.pub4|issn=1469-493X|pmid=33063850}}</ref> It is [[Generic drug|generic]] and sold under many brand names worldwide.<ref name=generics>Drugs.com [https://www.drugs.com/international/pentoxifylline.html drugs.com international listings for Pentoxifylline]. Page accessed Feb 1, 206</ref>
'''Pentoxifylline''', also known as '''oxpentifylline''', is a [[xanthine]] derivative used as a drug to treat muscle pain in people with [[peripheral artery disease]].<ref name=":0">{{cite journal | vauthors = Broderick C, Forster R, Abdel-Hadi M, Salhiyyah K | title = Pentoxifylline for intermittent claudication | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 10 | pages = CD005262 | date = October 2020 | pmid = 33063850 | pmc = 8094235 | doi = 10.1002/14651858.CD005262.pub4 }}</ref> It is [[Generic drug|generic]] and sold under many brand names worldwide.<ref name=generics>Drugs.com [https://www.drugs.com/international/pentoxifylline.html drugs.com international listings for Pentoxifylline]. Page accessed Feb 1, 206</ref>


== Medical uses ==
== 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 disease]]s.<ref name=":0" /> This is its only [[Food and Drug Administration|FDA]], [[Medicines and Healthcare products Regulatory Agency|MHRA]] and [[Therapeutic Goods Administration|TGA]]-labelled indication.<ref name = TGA/><ref name = DM>{{cite web|title=PENTOXIFYLLINE tablet, extended release [Apotex Corp.]|work=DailyMed|publisher=Apotex Corp.|date=February 2013|access-date=3 February 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=40ae2d9a-0d95-640d-0640-f76e7e1a13cb#nlm34067-9}}</ref><ref name = EMC>{{cite web|title=Trental 400 - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Sanofi|date=10 October 2013|access-date=3 February 2014|url=http://www.medicines.org.uk/emc/medicine/338/SPC/Trental+400/}}</ref> However, pentoxifylline is also recommended for [[off-label]] use as an adjunct to [[Elastic bandage|compression bandaging]] for the treatment of [[Venous ulcer|chronic venous leg ulcers]] by the [[Healthcare Improvement Scotland#Scottish Intercollegiate Guidelines Network|Scottish Intercollegiate Guidelines Network]] (SIGN) <ref>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}}</ref> as this has been shown to improve healing rates.<ref name="JullArroll2012">{{cite journal|last1=Jull|first1=Andrew B|last2=Arroll|first2=Bruce|last3=Parag|first3=Varsha|last4=Waters|first4=Jill|title=Pentoxifylline for treating venous leg ulcers|journal=Cochrane Database of Systematic Reviews|volume=12|pages=CD001733|year=2012|issn=1465-1858|doi=10.1002/14651858.CD001733.pub3|pmid=23235582|pmc=7061323}}</ref>
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 disease]]s.<ref name=":0" /> This is its only [[Food and Drug Administration|FDA]], [[Medicines and Healthcare products Regulatory Agency|MHRA]] and [[Therapeutic Goods Administration|TGA]]-labelled indication.<ref name = TGA/><ref name = DM>{{cite web|title=PENTOXIFYLLINE tablet, extended release [Apotex Corp.]|work=DailyMed|publisher=Apotex Corp.|date=February 2013|access-date=3 February 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=40ae2d9a-0d95-640d-0640-f76e7e1a13cb#nlm34067-9}}</ref><ref name = EMC>{{cite web|title=Trental 400 - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Sanofi|date=10 October 2013|access-date=3 February 2014|url=http://www.medicines.org.uk/emc/medicine/338/SPC/Trental+400/}}</ref> However, pentoxifylline is also recommended for [[off-label]] use as an adjunct to [[Elastic bandage|compression bandaging]] for the treatment of [[Venous ulcer|chronic venous leg ulcers]] by the [[Healthcare Improvement Scotland#Scottish Intercollegiate Guidelines Network|Scottish Intercollegiate Guidelines Network]] (SIGN) <ref>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}}</ref> as this has been shown to improve healing rates.<ref name="JullArroll2012">{{cite journal | vauthors = Jull AB, Arroll B, Parag V, Waters J | title = Pentoxifylline for treating venous leg ulcers | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD001733 | date = December 2012 | issue = 12 | pmid = 23235582 | pmc = 7061323 | doi = 10.1002/14651858.CD001733.pub3 }}</ref>


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.<ref>{{cite journal | vauthors = Zabel P, Entzian P, Dalhoff K, Schlaak M | title = Pentoxifylline in treatment of sarcoidosis | journal = American Journal of Respiratory and Critical Care Medicine | volume = 155 | issue = 5 | pages = 1665–1669 | date = May 1997 | pmid = 9154873 | doi = 10.1164/ajrccm.155.5.9154873 }}</ref><ref>{{cite journal | vauthors = Park MK, Babaali H, Gilbert-McClain LI, Stylianou M, Joo J, Moss J, Manganiello VC | title = Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis | journal = Sarcoidosis, Vasculitis, and Diffuse Lung Diseases | volume = 26 | issue = 2 | pages = 121–131 | date = July 2009 | pmid = 20560292 | pmc = 2946799 }}</ref><ref>{{cite journal | vauthors = Tong Z, Dai H, Chen B, Abdoh Z, Guzman J, Costabel U | title = Inhibition of cytokine release from alveolar macrophages in pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone | journal = Chest | volume = 124 | issue = 4 | pages = 1526–1532 | date = October 2003 | pmid = 14555589 | doi = 10.1378/chest.124.4.1526 }}</ref>
Pentoxifylline has also been shown to be of benefit in [[alcoholic hepatitis]], with some studies demonstrating a reduction in risk of [[hepatorenal syndrome]].{{citation needed|date=September 2019}}
It has further been used to treat immunologic reactions to [[leprosy]] with some success.<ref>{{cite journal | vauthors = Legendre DP, Muzny CA, Swiatlo E | title = Hansen's disease (Leprosy): current and future pharmacotherapy and treatment of disease-related immunologic reactions | journal = Pharmacotherapy | volume = 32 | issue = 1 | pages = 27–37 | date = January 2012 | pmid = 22392826 | doi = 10.1002/PHAR.1009 | s2cid = 46569413 }}</ref>
Benefit in [[alcoholic hepatitis]] was shown, with some studies demonstrating a reduction in risk of [[hepatorenal syndrome]].{{citation needed|date=September 2019}}
For [[in vitro fertilization]], Pentoxifylline has been used to improve [[sperm]] quality and motility<ref>{{cite journal | vauthors = Mahaldashtian M, Khalili MA, Nottola SA, Woodward B, Macchiarelli G, Miglietta S | title = Does in vitro application of pentoxifylline have beneficial effects in assisted male reproduction? | journal = Andrologia | volume = 53 | issue = 1 | pages = e13722 | date = February 2021 | pmid = 33112447 | doi = 10.1111/and.13722 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Baldini D, Ferri D, Baldini GM, Lot D, Catino A, Vizziello D, Vizziello G | title = Sperm Selection for ICSI: Do We Have a Winner? | journal = Cells | volume = 10 | issue = 12 | date = December 2021 | page = 3566 | pmid = 34944074 | doi = 10.3390/cells10123566 | pmc = 8700516 | doi-access = free }}</ref> and as safe oral drug in the treatment of male [[infertility]] with [[erectile dysfunction]].<ref>{{cite journal | vauthors = Lu Y, Su H, Zhang J, Wang Y, Li H | title = Treatment of Poor Sperm Quality and Erectile Dysfunction With Oral Pentoxifylline: A Systematic Review | journal = Frontiers in Pharmacology | date = 2022 | volume = 12 | pages = 789787 | pmid = 35095501 | doi = 10.3389/fphar.2021.789787 | pmc = 8790020 | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref><ref>{{cite journal | vauthors = Korenman SG, Viosca SP | title = Treatment of vasculogenic sexual dysfunction with pentoxifylline | journal = Journal of the American Geriatrics Society | volume = 41 | issue = 4 | pages = 363–366 | date = April 1993 | pmid = 8463520 | doi = 10.1111/j.1532-5415.1993.tb06941.x | s2cid = 35396795 }}</ref>

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]].<ref>{{cite journal | vauthors = Hosseini F, Mohammadbeigi A, Aghaali M, Borujerdi R, Parham M | title = Effect of pentoxifylline on diabetic distal polyneuropathy in type 2 diabetic patients: A randomized trial | journal = Journal of Research in Medical Sciences | volume = 24 | issue = 1 | pages = 89 | date = 2019 | pmid = 31741661 | pmc = 6856542 | doi = 10.4103/jrms.JRMS_115_18 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Page JC, Chen EY | title = Management of painful diabetic neuropathy. A treatment algorithm | journal = Journal of the American Podiatric Medical Association | volume = 87 | issue = 8 | pages = 370–379 | date = August 1997 | pmid = 9274092 | doi = 10.7547/87507315-87-8-370 }}</ref> 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.<ref>{{cite journal | vauthors = de Carvalho EF, Bertotti M, Migliorati CA, Rocha AC | title = Cilostazol and Tocopherol in the Management of Medication-Related Osteonecrosis of the Jaw: New Insights From a Case Report | journal = Journal of Oral and Maxillofacial Surgery | volume = 79 | issue = 12 | pages = 2499–2506 | date = December 2021 | doi = 10.1016/j.joms.2021.06.036 | pmid = 34339622 | s2cid = 236884968 | url = https://www.practiceupdate.com/content/adjunctive-effect-of-pentoxifylline-and-tocopherol-in-the-management-of-medication-related-osteonecrosis-of-the-jaw/155064 | access-date = 2023-09-04 }}</ref>

Pentoxifylline may be used transdermally for cellulite treatment.


==Adverse effects==
==Adverse effects==
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== Mechanism ==
== Mechanism ==
Like other methylated [[xanthine|xanthine derivatives]], pentoxifylline is a competitive nonselective [[phosphodiesterase inhibitor]]<ref name="PDEs-Essayan">{{cite journal |vauthors=Essayan DM |title=Cyclic nucleotide phosphodiesterases |journal=The Journal of Allergy and Clinical Immunology |volume=108 |issue=5 |pages=671–80 |year=2001 |pmid=11692087 |doi=10.1067/mai.2001.119555 }}</ref> which raises intracellular [[Cyclic adenosine monophosphate|cAMP]], activates [[cAMP-dependent protein kinase|PKA]], [[TNF inhibitor|inhibits TNF]]<ref name="PTX-Deree">{{cite journal |vauthors=Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R |title=Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition |journal=Clinics |volume=63 |issue=3 |pages=321–8 |year=2008 |pmid=18568240 |pmc=2664230 |doi=10.1590/S1807-59322008000300006 }}</ref><ref name="pmid9927365">{{cite journal |vauthors=Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U |title=Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages |journal=American Journal of Respiratory and Critical Care Medicine |volume=159 |issue=2 |pages=508–11 |year=1999 |pmid=9927365 |doi=10.1164/ajrccm.159.2.9804085 }}</ref> and [[leukotriene]]<ref name="LT-Peters-Golden">{{cite journal |vauthors=Peters-Golden M, Canetti C, Mancuso P, Coffey MJ |title=Leukotrienes: underappreciated mediators of innate immune responses |journal=Journal of Immunology |volume=174 |issue=2 |pages=589–94 |year=2005 |pmid=15634873 |doi=10.4049/jimmunol.174.2.589 |doi-access=free }}</ref> synthesis, and [[Anti-inflammatory|reduces inflammation]] and [[innate immunity]].<ref name="LT-Peters-Golden"/> 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.<ref>{{cite journal |vauthors=Ward A, Clissold SP |title=Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy |journal=Drugs |volume=34 |issue=1 |pages=50–97 |year=1987 |pmid=3308412 |doi=10.2165/00003495-198734010-00003 }}</ref> Pentoxifylline is also an antagonist at [[adenosine]] 2 receptors.<ref name="pmid18220696">{{cite journal |vauthors=Rodríguez-Morán M, Guerrero-Romero F |title=Efficacy of pentoxifylline in the management of microalbuminuria in patients with diabetes |journal=Current Diabetes Reviews |volume=4 |issue=1 |pages=55–62 |year=2008 |pmid=18220696 |doi=10.2174/157339908783502343 }}</ref>
Like other methylated [[xanthine|xanthine derivatives]], pentoxifylline is a competitive nonselective [[phosphodiesterase inhibitor]]<ref name="PDEs-Essayan">{{cite journal | vauthors = Essayan DM | title = Cyclic nucleotide phosphodiesterases | journal = The Journal of Allergy and Clinical Immunology | volume = 108 | issue = 5 | pages = 671–680 | date = November 2001 | pmid = 11692087 | doi = 10.1067/mai.2001.119555 | doi-access = free }}</ref> which raises intracellular [[Cyclic adenosine monophosphate|cAMP]], activates [[cAMP-dependent protein kinase|PKA]], [[TNF inhibitor|inhibits TNF]]<ref name="PTX-Deree">{{cite journal | vauthors = Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R | title = Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition | journal = Clinics | volume = 63 | issue = 3 | pages = 321–328 | date = June 2008 | pmid = 18568240 | pmc = 2664230 | doi = 10.1590/S1807-59322008000300006 }}</ref><ref name="pmid9927365">{{cite journal | vauthors = Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U | title = Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages | journal = American Journal of Respiratory and Critical Care Medicine | volume = 159 | issue = 2 | pages = 508–511 | date = February 1999 | pmid = 9927365 | doi = 10.1164/ajrccm.159.2.9804085 }}</ref> and [[leukotriene]]<ref name="LT-Peters-Golden">{{cite journal | vauthors = Peters-Golden M, Canetti C, Mancuso P, Coffey MJ | title = Leukotrienes: underappreciated mediators of innate immune responses | journal = Journal of Immunology | volume = 174 | issue = 2 | pages = 589–594 | date = January 2005 | pmid = 15634873 | doi = 10.4049/jimmunol.174.2.589 | doi-access = free }}</ref> synthesis, and [[Anti-inflammatory|reduces inflammation]] and [[innate immunity]].<ref name="LT-Peters-Golden"/> 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.<ref>{{cite journal | vauthors = Ward A, Clissold SP | title = Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy | journal = Drugs | volume = 34 | issue = 1 | pages = 50–97 | date = July 1987 | pmid = 3308412 | doi = 10.2165/00003495-198734010-00003 | s2cid = 195697501 }}</ref> Pentoxifylline is also an antagonist at [[adenosine]] 2 receptors.<ref name="pmid18220696">{{cite journal | vauthors = Rodríguez-Morán M, Guerrero-Romero F | title = Efficacy of pentoxifylline in the management of microalbuminuria in patients with diabetes | journal = Current Diabetes Reviews | volume = 4 | issue = 1 | pages = 55–62 | date = February 2008 | pmid = 18220696 | doi = 10.2174/157339908783502343 }}</ref>


==Research==
==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.<ref>{{cite journal |vauthors=Li W, Zheng L, Sheng C, Cheng X, Qing L, Qu S |title=Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease |journal=Lipids in Health and Disease |volume=10 |pages=49 |year=2011 |pmid=21477300 |pmc=3088890 |doi=10.1186/1476-511X-10-49 }}</ref> Animal studies have been conducted exploring the use of pentoxifylline for [[erectile dysfunction]]<ref>{{cite journal | pmid=25392014| pmc=4430197| year=2015| last1=Anele| first1=U. A.| title=Molecular pathophysiology of priapism: Emerging targets| journal=Current Drug Targets| volume=16| issue=5| pages=474–83| last2=Morrison| first2=B. F.| last3=Burnett| first3=A. L.| doi=10.2174/1389450115666141111111842}}</ref> and [[hearing loss]].<ref>{{cite journal |last1=Latoni |first1=J. |last2=Shivapuja |first2=B. |last3=Seidman |first3=M. D. |last4=Quirk |first4=W. S. |title=Pentoxifylline maintains cochlear microcirculation and attenuates temporary threshold shifts following acoustic overstimulation. |journal=Acta Oto-Laryngologica |date=May 1996 |volume=116 |issue=3 |pages=388–94 |doi=10.3109/00016489609137862 |pmid=8790737 }}</ref> Human studies have been conducted for [[Peyronie's disease]].<ref>{{cite journal | pmid=26579268| pmc=4149188| year=2011| last1=El-Sakka| first1=A. I.| title=Reversion of penile fibrosis: Current information and a new horizon| journal=Arab Journal of Urology| volume=9| issue=1| pages=49–55| doi=10.1016/j.aju.2011.03.013}}</ref>
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.<ref>{{cite journal | vauthors = Li W, Zheng L, Sheng C, Cheng X, Qing L, Qu S | title = Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease | journal = Lipids in Health and Disease | volume = 10 | pages = 49 | date = April 2011 | pmid = 21477300 | pmc = 3088890 | doi = 10.1186/1476-511X-10-49 | doi-access = free }}</ref> Animal studies have been conducted exploring the use of pentoxifylline for [[erectile dysfunction]]<ref>{{cite journal | vauthors = Anele UA, Morrison BF, Burnett AL | title = Molecular pathophysiology of priapism: emerging targets | journal = Current Drug Targets | volume = 16 | issue = 5 | pages = 474–483 | year = 2015 | pmid = 25392014 | pmc = 4430197 | doi = 10.2174/1389450115666141111111842 }}</ref> and [[hearing loss]].<ref>{{cite journal | vauthors = Latoni J, Shivapuja B, Seidman MD, Quirk WS | title = Pentoxifylline maintains cochlear microcirculation and attenuates temporary threshold shifts following acoustic overstimulation | journal = Acta Oto-Laryngologica | volume = 116 | issue = 3 | pages = 388–394 | date = May 1996 | pmid = 8790737 | doi = 10.3109/00016489609137862 }}</ref> Human studies have been conducted for [[Peyronie's disease]].<ref>{{cite journal | vauthors = El-Sakka AI | title = Reversion of penile fibrosis: Current information and a new horizon | journal = Arab Journal of Urology | volume = 9 | issue = 1 | pages = 49–55 | date = March 2011 | pmid = 26579268 | pmc = 4149188 | doi = 10.1016/j.aju.2011.03.013 }}</ref>


Pentoxifylline, in combination with [[tocopherol]] and [[clodronate]], has been found to heal [[refractory]] [[osteoradionecrosis]] of the jaw,<ref>Delanian, S., Chatel, C., Porcher, R., Depondt, J. and Lefaix, J.L., 2011. 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), pp.832-839.</ref>
Pentoxifylline, in combination with [[tocopherol]] and [[clodronate]], has been found to heal refractory [[osteoradionecrosis]] of the jaw,<ref name="pmid20638190">{{cite journal | vauthors = Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL | title = Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial | journal = International Journal of Radiation Oncology, Biology, Physics | volume = 80 | issue = 3 | pages = 832–9 | date = July 2011 | pmid = 20638190 | doi = 10.1016/j.ijrobp.2010.03.029 | doi-access = free }}</ref>
and to be prophylactic against osteoradionecrosis.<ref>Patel, V., Gadiwalla, Y., Sassoon, I., Sproat, C., Kwok, J. and McGurk, M., 2016. Prophylactic use of pentoxifylline and tocopherol in patients who require dental extractions after radiotherapy for cancer of the head and neck. British Journal of Oral and Maxillofacial Surgery, 54(5), pp.547-550.</ref>
and to be prophylactic against osteoradionecrosis.<ref name="pmid26975577">{{cite journal | vauthors = Patel V, Gadiwalla Y, Sassoon I, Sproat C, Kwok J, McGurk M | title = Prophylactic use of pentoxifylline and tocopherol in patients who require dental extractions after radiotherapy for cancer of the head and neck | journal = The British Journal of Oral & Maxillofacial Surgery | volume = 54 | issue = 5 | pages = 547–50 | date = June 2016 | pmid = 26975577 | doi = 10.1016/j.bjoms.2016.02.024 }}</ref>


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 <abbr>randomisation</abbr> techniques or how treatment allocation was concealed, did not provide adequate information to permit judgement of selective reporting and did not report <abbr>blinding</abbr> of <abbr>outcome</abbr> assessors. Given all these factors, the role of pentoxifylline in intermittent <abbr>claudication</abbr> remains uncertain, although this medication was generally well tolerated by participants".<ref>{{Cite journal|last1=Salhiyyah|first1=Kareem|last2=Forster|first2=Rachel|last3=Senanayake|first3=Eshan|last4=Abdel-Hadi|first4=Mohammed|last5=Booth|first5=Andrew|last6=Michaels|first6=Jonathan A|date=2015-09-29|title=Pentoxifylline for intermittent claudication|journal=Cochrane Database of Systematic Reviews|volume=9|language=en|issue=9|pages=CD005262|doi=10.1002/14651858.cd005262.pub3|pmid=26417854|issn=1465-1858|pmc=6513423}}</ref>{{Update inline|reason=Updated version https://www.ncbi.nlm.nih.gov/pubmed/33063850|date = December 2020}}
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 <abbr>randomisation</abbr> techniques or how treatment allocation was concealed, did not provide adequate information to permit judgement of selective reporting and did not report <abbr>blinding</abbr> of <abbr>outcome</abbr> assessors. Given all these factors, the role of pentoxifylline in intermittent <abbr>claudication</abbr> remains uncertain, although this medication was generally well tolerated by participants".<ref>{{cite journal | vauthors = Salhiyyah K, Forster R, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA | title = Pentoxifylline for intermittent claudication | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | pages = CD005262 | date = September 2015 | pmid = 26417854 | pmc = 6513423 | doi = 10.1002/14651858.cd005262.pub3 }}</ref>{{Update inline|reason=Updated version https://www.ncbi.nlm.nih.gov/pubmed/33063850|date = December 2020}}


==See also==
== See also ==
* [[Lisofylline]], an active metabolite of pentoxifylline
* [[Lisofylline]], an active metabolite of pentoxifylline
*[[Propentofylline]]
*[[Propentofylline]]

Latest revision as of 06:09, 19 May 2024

Pentoxifylline
Clinical data
Pronunciation/ˌpɛntɒkˈsɪfɪln, -ɪn/
Trade namesTrental, many other names worldwide[1]
Other namesoxpentifylline (former AAN)[2]
AHFS/Drugs.comMonograph
MedlinePlusa685027
License data
Pregnancy
category
  • AU: B1
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability10–30%[3]
MetabolismHepatic and via erythrocytes
Elimination half-life0.4–0.8 hours (1–1.6 hours for active metabolite)[3]
ExcretionUrine (95%), faeces (<4%)[3]
Identifiers
  • 3,7-Dimethyl-1-(5-oxohexyl)purine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.026.704 Edit this at Wikidata
Chemical and physical data
FormulaC13H18N4O3
Molar mass278.312 g·mol−1
3D model (JSmol)
  • O=C2N(c1ncn(c1C(=O)N2CCCCC(=O)C)C)C
  • InChI=1S/C13H18N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8H,4-7H2,1-3H3 checkY
  • Key:BYPFEZZEUUWMEJ-UHFFFAOYSA-N checkY
  (verify)

Pentoxifylline, also known as oxpentifylline, is a xanthine derivative used as a drug to treat muscle pain in people with peripheral artery disease.[4] It is generic and sold under many brand names worldwide.[1]

Medical uses

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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.[4] This is its only FDA, MHRA and TGA-labelled indication.[2][5][6] 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) [7] as this has been shown to improve healing rates.[8]

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.[9][10][11] It has further been used to treat immunologic reactions to leprosy with some success.[12] Benefit in alcoholic hepatitis was shown, with some studies demonstrating a reduction in risk of hepatorenal syndrome.[citation needed] For in vitro fertilization, Pentoxifylline has been used to improve sperm quality and motility[13][14] and as safe oral drug in the treatment of male infertility with erectile dysfunction.[15][16]

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.[17] 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.[18] 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.[19]

Pentoxifylline may be used transdermally for cellulite treatment.

Adverse effects

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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.[2][3][5][6]

Contraindications include intolerance to pentoxifylline or other xanthine derivatives, recent retinal or cerebral haemorrhage, and risk factors for haemorrhage.[3]

Mechanism

[edit]

Like other methylated xanthine derivatives, pentoxifylline is a competitive nonselective phosphodiesterase inhibitor[20] which raises intracellular cAMP, activates PKA, inhibits TNF[21][22] and leukotriene[23] synthesis, and reduces inflammation and innate immunity.[23] 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.[24] Pentoxifylline is also an antagonist at adenosine 2 receptors.[25]

Research

[edit]

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.[26] Animal studies have been conducted exploring the use of pentoxifylline for erectile dysfunction[27] and hearing loss.[28] Human studies have been conducted for Peyronie's disease.[29]

Pentoxifylline, in combination with tocopherol and clodronate, has been found to heal refractory osteoradionecrosis of the jaw,[30] and to be prophylactic against osteoradionecrosis.[31]

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".[32][needs update]

See also

[edit]
  • 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

[edit]
  1. ^ a b Drugs.com drugs.com international listings for Pentoxifylline. Page accessed Feb 1, 206
  2. ^ a b c "PRODUCT INFORMATION TRENTAL® 400" (PDF). TGA eBusiness Services. sanofi-aventis australia pty limited. 25 March 2010. Retrieved 3 February 2014.
  3. ^ a b c d e "Trental, Pentoxil (pentoxifylline) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 February 2014.
  4. ^ a b Broderick C, Forster R, Abdel-Hadi M, Salhiyyah K (October 2020). "Pentoxifylline for intermittent claudication". The Cochrane Database of Systematic Reviews. 2020 (10): CD005262. doi:10.1002/14651858.CD005262.pub4. PMC 8094235. PMID 33063850.
  5. ^ a b "PENTOXIFYLLINE tablet, extended release [Apotex Corp.]". DailyMed. Apotex Corp. February 2013. Retrieved 3 February 2014.
  6. ^ a b "Trental 400 - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Sanofi. 10 October 2013. Retrieved 3 February 2014.
  7. ^ 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
  8. ^ Jull AB, Arroll B, Parag V, Waters J (December 2012). "Pentoxifylline for treating venous leg ulcers". The Cochrane Database of Systematic Reviews. 12 (12): CD001733. doi:10.1002/14651858.CD001733.pub3. PMC 7061323. PMID 23235582.
  9. ^ Zabel P, Entzian P, Dalhoff K, Schlaak M (May 1997). "Pentoxifylline in treatment of sarcoidosis". American Journal of Respiratory and Critical Care Medicine. 155 (5): 1665–1669. doi:10.1164/ajrccm.155.5.9154873. PMID 9154873.
  10. ^ Park MK, Babaali H, Gilbert-McClain LI, Stylianou M, Joo J, Moss J, Manganiello VC (July 2009). "Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis". Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 26 (2): 121–131. PMC 2946799. PMID 20560292.
  11. ^ Tong Z, Dai H, Chen B, Abdoh Z, Guzman J, Costabel U (October 2003). "Inhibition of cytokine release from alveolar macrophages in pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone". Chest. 124 (4): 1526–1532. doi:10.1378/chest.124.4.1526. PMID 14555589.
  12. ^ Legendre DP, Muzny CA, Swiatlo E (January 2012). "Hansen's disease (Leprosy): current and future pharmacotherapy and treatment of disease-related immunologic reactions". Pharmacotherapy. 32 (1): 27–37. doi:10.1002/PHAR.1009. PMID 22392826. S2CID 46569413.
  13. ^ Mahaldashtian M, Khalili MA, Nottola SA, Woodward B, Macchiarelli G, Miglietta S (February 2021). "Does in vitro application of pentoxifylline have beneficial effects in assisted male reproduction?". Andrologia. 53 (1): e13722. doi:10.1111/and.13722. PMID 33112447.
  14. ^ Baldini D, Ferri D, Baldini GM, Lot D, Catino A, Vizziello D, Vizziello G (December 2021). "Sperm Selection for ICSI: Do We Have a Winner?". Cells. 10 (12): 3566. doi:10.3390/cells10123566. PMC 8700516. PMID 34944074.
  15. ^ Lu Y, Su H, Zhang J, Wang Y, Li H (2022). "Treatment of Poor Sperm Quality and Erectile Dysfunction With Oral Pentoxifylline: A Systematic Review". Frontiers in Pharmacology. 12: 789787. doi:10.3389/fphar.2021.789787. PMC 8790020. PMID 35095501. This article incorporates text from this source, which is available under the CC BY 4.0 license.
  16. ^ Korenman SG, Viosca SP (April 1993). "Treatment of vasculogenic sexual dysfunction with pentoxifylline". Journal of the American Geriatrics Society. 41 (4): 363–366. doi:10.1111/j.1532-5415.1993.tb06941.x. PMID 8463520. S2CID 35396795.
  17. ^ Hosseini F, Mohammadbeigi A, Aghaali M, Borujerdi R, Parham M (2019). "Effect of pentoxifylline on diabetic distal polyneuropathy in type 2 diabetic patients: A randomized trial". Journal of Research in Medical Sciences. 24 (1): 89. doi:10.4103/jrms.JRMS_115_18. PMC 6856542. PMID 31741661.
  18. ^ Page JC, Chen EY (August 1997). "Management of painful diabetic neuropathy. A treatment algorithm". Journal of the American Podiatric Medical Association. 87 (8): 370–379. doi:10.7547/87507315-87-8-370. PMID 9274092.
  19. ^ de Carvalho EF, Bertotti M, Migliorati CA, Rocha AC (December 2021). "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. doi:10.1016/j.joms.2021.06.036. PMID 34339622. S2CID 236884968. Retrieved 2023-09-04.
  20. ^ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology. 108 (5): 671–680. doi:10.1067/mai.2001.119555. PMID 11692087.
  21. ^ Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics. 63 (3): 321–328. doi:10.1590/S1807-59322008000300006. PMC 2664230. PMID 18568240.
  22. ^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine. 159 (2): 508–511. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.
  23. ^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (January 2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology. 174 (2): 589–594. doi:10.4049/jimmunol.174.2.589. PMID 15634873.
  24. ^ Ward A, Clissold SP (July 1987). "Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy". Drugs. 34 (1): 50–97. doi:10.2165/00003495-198734010-00003. PMID 3308412. S2CID 195697501.
  25. ^ Rodríguez-Morán M, Guerrero-Romero F (February 2008). "Efficacy of pentoxifylline in the management of microalbuminuria in patients with diabetes". Current Diabetes Reviews. 4 (1): 55–62. doi:10.2174/157339908783502343. PMID 18220696.
  26. ^ Li W, Zheng L, Sheng C, Cheng X, Qing L, Qu S (April 2011). "Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease". Lipids in Health and Disease. 10: 49. doi:10.1186/1476-511X-10-49. PMC 3088890. PMID 21477300.
  27. ^ Anele UA, Morrison BF, Burnett AL (2015). "Molecular pathophysiology of priapism: emerging targets". Current Drug Targets. 16 (5): 474–483. doi:10.2174/1389450115666141111111842. PMC 4430197. PMID 25392014.
  28. ^ Latoni J, Shivapuja B, Seidman MD, Quirk WS (May 1996). "Pentoxifylline maintains cochlear microcirculation and attenuates temporary threshold shifts following acoustic overstimulation". Acta Oto-Laryngologica. 116 (3): 388–394. doi:10.3109/00016489609137862. PMID 8790737.
  29. ^ El-Sakka AI (March 2011). "Reversion of penile fibrosis: Current information and a new horizon". Arab Journal of Urology. 9 (1): 49–55. doi:10.1016/j.aju.2011.03.013. PMC 4149188. PMID 26579268.
  30. ^ Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL (July 2011). "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. doi:10.1016/j.ijrobp.2010.03.029. PMID 20638190.
  31. ^ Patel V, Gadiwalla Y, Sassoon I, Sproat C, Kwok J, McGurk M (June 2016). "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. doi:10.1016/j.bjoms.2016.02.024. PMID 26975577.
  32. ^ Salhiyyah K, Forster R, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA (September 2015). "Pentoxifylline for intermittent claudication". The Cochrane Database of Systematic Reviews. 9 (9): CD005262. doi:10.1002/14651858.cd005262.pub3. PMC 6513423. PMID 26417854.
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