Chemistry:Pentoxifylline

From HandWiki
Short description: Chemical compound
Pentoxifylline
Pentoxifylline.svg
Pentoxifylline xtal 2005 ball-and-stick.png
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
  • US: C (Risk not ruled out)
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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC13H18N4O3
Molar mass278.312 g·mol−1
3D model (JSmol)
  (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

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 and 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]

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.[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

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

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

  • 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 Drugs.com drugs.com international listings for Pentoxifylline. Page accessed Feb 1, 206
  2. 2.0 2.1 2.2 "PRODUCT INFORMATION TRENTAL® 400" (PDF). TGA eBusiness Services. sanofi-aventis australia pty limited. 25 March 2010. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06086-3. 
  3. 3.0 3.1 3.2 3.3 3.4 "Trental, Pentoxil (pentoxifylline) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/trental-pentoxil-pentoxifylline-342179#showall. 
  4. 4.0 4.1 "Pentoxifylline for intermittent claudication". The Cochrane Database of Systematic Reviews 2020 (10): CD005262. October 2020. doi:10.1002/14651858.CD005262.pub4. PMID 33063850. 
  5. 5.0 5.1 "PENTOXIFYLLINE tablet, extended release [Apotex Corp."]. DailyMed. Apotex Corp.. February 2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=40ae2d9a-0d95-640d-0640-f76e7e1a13cb#nlm34067-9. 
  6. 6.0 6.1 "Trental 400 - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Sanofi. 10 October 2013. http://www.medicines.org.uk/emc/medicine/338/SPC/Trental+400/. 
  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. "Pentoxifylline for treating venous leg ulcers". The Cochrane Database of Systematic Reviews 12 (12): CD001733. December 2012. doi:10.1002/14651858.CD001733.pub3. PMID 23235582. 
  9. "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. 
  10. "Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis". Sarcoidosis, Vasculitis, and Diffuse Lung Diseases 26 (2): 121–131. July 2009. PMID 20560292. 
  11. "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. 
  12. "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. 
  13. "Does in vitro application of pentoxifylline have beneficial effects in assisted male reproduction?". Andrologia 53 (1): e13722. February 2021. doi:10.1111/and.13722. PMID 33112447. 
  14. "Sperm Selection for ICSI: Do We Have a Winner?". Cells 10 (12): 3566. December 2021. doi:10.3390/cells10123566. PMID 34944074. 
  15. "Treatment of Poor Sperm Quality and Erectile Dysfunction With Oral Pentoxifylline: A Systematic Review". Frontiers in Pharmacology 12: 789787. 2022. doi:10.3389/fphar.2021.789787. PMID 35095501. 
  16. "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. 
  17. "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. 
  18. "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. 
  19. "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 2023-09-04. 
  20. "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology 108 (5): 671–680. November 2001. doi:10.1067/mai.2001.119555. PMID 11692087. 
  21. "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. doi:10.1590/S1807-59322008000300006. PMID 18568240. 
  22. "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. 
  23. 23.0 23.1 "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology 174 (2): 589–594. January 2005. doi:10.4049/jimmunol.174.2.589. PMID 15634873. 
  24. "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. 
  25. "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. 
  26. "Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease". Lipids in Health and Disease 10: 49. April 2011. doi:10.1186/1476-511X-10-49. PMID 21477300. 
  27. "Molecular pathophysiology of priapism: emerging targets". Current Drug Targets 16 (5): 474–483. 2015. doi:10.2174/1389450115666141111111842. PMID 25392014. 
  28. "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. 
  29. "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. 
  30. "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. doi:10.1016/j.ijrobp.2010.03.029. PMID 20638190. 
  31. "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. doi:10.1016/j.bjoms.2016.02.024. PMID 26975577. 
  32. "Pentoxifylline for intermittent claudication". The Cochrane Database of Systematic Reviews 9 (9): CD005262. September 2015. doi:10.1002/14651858.cd005262.pub3. PMID 26417854. 

External links