Pentoxifylline

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Pentoxifylline
Pentoxifylline.svg
Pentoxifylline xtal 2005 ball-and-stick.png
Clinical data
Pronunciation /ˌpɛntɒkˈsɪfɪliːn,-ɪn/
Trade names Trental, many other names worldwide [1]
Other namesoxpentifylline (former AAN) [2]
AHFS/Drugs.com Monograph
MedlinePlus a685027
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 10–30% [3]
Metabolism Hepatic and via erythrocytes
Elimination half-life 0.4–0.8 hours (1–1.6 hours for active metabolite) [3]
Excretion Urine (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 InfoCard 100.026.704 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H18N4O3
Molar mass 278.312 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 Yes check.svgY
  • Key:BYPFEZZEUUWMEJ-UHFFFAOYSA-N Yes check.svgY
   (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]

Contents

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]

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. [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

Related Research Articles

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Xanthine</span> Chemical compound

Xanthine is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, theophylline, and theobromine.

<span class="mw-page-title-main">Theophylline</span> Drug used to treat respiratory diseases

Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other methylxanthine drugs. Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.

<span class="mw-page-title-main">Benign prostatic hyperplasia</span> Noncancerous increase in size of the prostate gland

Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss of bladder control. Complications can include urinary tract infections, bladder stones, and chronic kidney problems.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

<span class="mw-page-title-main">Sarcoidosis</span> Medical condition

Sarcoidosis is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly affected are the eyes, liver, heart, and brain, though any organ can be affected. The signs and symptoms depend on the organ involved. Often, no, or only mild, symptoms are seen. When it affects the lungs, wheezing, coughing, shortness of breath, or chest pain may occur. Some may have Löfgren syndrome with fever, large lymph nodes, arthritis, and a rash known as erythema nodosum.

<span class="mw-page-title-main">Infliximab</span> Biopharmaceutical drug for autommune disorders

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

<span class="mw-page-title-main">Tadalafil</span> Medication used to treat erectile dysfunction

Tadalafil, sold under the brand name Cialis among others, is a medication used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. It is taken by mouth. Onset is typically within half an hour and the duration is up to 36 hours.

<span class="mw-page-title-main">Peripheral artery disease</span> Medical condition

Peripheral artery disease (PAD) is a vascular disorder abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms.

<span class="mw-page-title-main">Duloxetine</span> Antidepressant medication used also for treatment of anxiety and chronic pain

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth.

<span class="mw-page-title-main">Peripheral neuropathy</span> Nervous system disease affecting nerves beyond the brain and spinal cord

Peripheral neuropathy, often shortened to neuropathy, is a general term describing damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerves are affected. Neuropathy affecting motor, sensory, or autonomic nerves result in different symptoms. More than one type of nerve may be affected simultaneously. Peripheral neuropathy may be acute or chronic, and may be reversible or permanent.

Intermittent claudication, also known as vascular claudication, is a symptom that describes muscle pain on mild exertion, classically in the calf muscle, which occurs during exercise, such as walking, and is relieved by a short period of rest. It is classically associated with early-stage peripheral artery disease, and can progress to critical limb ischemia unless treated or risk factors are modified and maintained.

<span class="mw-page-title-main">PDE5 inhibitor</span> Vasodilating drug

A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in Homo sapiens

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Aminophylline</span> Chemical compound

Aminophylline is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

<span class="mw-page-title-main">IBMX</span> Chemical compound

IBMX (3-isobutyl-1-methylxanthine), like other methylated xanthine derivatives, is both a:

  1. competitive non-selective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNFα and leukotriene synthesis, and reduces inflammation and innate immunity, and
  2. nonselective adenosine receptor antagonist.
<span class="mw-page-title-main">Propentofylline</span> Chemical compound

Propentofylline is a xanthine derivative drug with purported neuroprotective effects.

<span class="mw-page-title-main">Diabetic foot</span> Medical condition

A diabetic foot disease is any condition that results directly from peripheral artery disease (PAD) or sensory neuropathy affecting the feet of people living with diabetes. Diabetic foot conditions can be acute or chronic complications of diabetes. Presence of several characteristic diabetic foot pathologies such as infection, diabetic foot ulcer and neuropathic osteoarthropathy is called diabetic foot syndrome. The resulting bone deformity is known as Charcot foot.

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

References

  1. 1 2 Drugs.com drugs.com international listings for Pentoxifylline. Page accessed Feb 1, 206
  2. 1 2 3 "PRODUCT INFORMATION TRENTAL® 400" (PDF). TGA eBusiness Services. sanofi-aventis australia pty limited. 25 March 2010. Retrieved 3 February 2014.
  3. 1 2 3 4 5 "Trental, Pentoxil (pentoxifylline) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 February 2014.
  4. 1 2 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. 1 2 "PENTOXIFYLLINE tablet, extended release [Apotex Corp.]". DailyMed. Apotex Corp. February 2013. Retrieved 3 February 2014.
  6. 1 2 "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.
  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. 1 2 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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