title: Pentoxifylline in preterm neonates: a systematic review.
abstract: Sepsis, necrotizing enterocolitis (NEC), and chronic lung disease (CLD) in preterm neonates are associated with significant mortality and morbidity, including long-term neurodevelopmental impairment and socioeconomic burden. Safe and effective drugs for the prevention and treatment of these conditions are urgently needed. Pentoxifylline, a synthetic theobromine derivative, is a non-steroidal immunomodulating agent with unique hemorrheologic effects which has been used in a range of infectious, vascular, and inflammatory conditions in adults and children. The unique properties of pentoxifylline explain its potential benefits in preterm neonates with sepsis, NEC, and CLD, conditions characterized by activation of the inflammatory cytokine cascade, free radical toxicity, and impaired microcirculation. Pentoxifylline has anti-inflammatory properties resulting from inhibition of erythrocyte phosphodiesterase. It lowers blood viscosity and improves microcirculation and tissue perfusion. As a phosphodiesterase inhibitor, pentoxifylline downregulates pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interferon-gamma. Methylxanthines, including caffeine, theophylline, and theobromine are relatively non-toxic drugs; of these, theobromine is the least toxic. Pentoxifylline-related significant adverse events are thus very rare. Unlike other methylxanthines, pentoxifylline does not have significant cardiac and bronchodilating effects at therapeutic doses. Although it is contraindicated in adults with recent cerebral hemorrhage due to its effect on platelets, red blood cells, and plasma fibrinogen levels, no significant adverse effects including thrombocytopenia and bleeding have been reported in critically ill preterm neonates with sepsis or NEC after treatment with pentoxifylline. Based on data from pilot randomized trials and observational studies, our systematic review suggests that pentoxifylline may reduce mortality and/or morbidity in preterm neonates with sepsis, NEC, and CLD. Results of experimental studies also indicate that pentoxifylline may potentially be beneficial in meconium aspiration syndrome and hypoxic ischemic encephalopathy. Given the substantial burden of sepsis, NEC, and CLD in high-risk preterm neonates, and the findings of this systematic review, pentoxifylline needs to be evaluated urgently as a preventative and therapeutic agent for these conditions in randomized controlled trials that can detect minimal clinically significant effect sizes. Further clinical and experimental studies are also necessary to evaluate whether pentoxifylline is safe and effective in meconium aspiration syndrome and hypoxic ischemic encephalopathy.
authors.affiliation: King Edward Memorial Hospital, Perth, Western Australia, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Harris
authors.forename: Sven M
authors.initials: SM
authors.lastname: Schulzke
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Patole
mesh_terms: D000818:Animals; D006801:Humans; D007231:Infant, Newborn; D008171:Lung Diseases / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control; D008471:Meconium Aspiration Syndrome / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control; D010431:Pentoxifylline / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010547:Persistent Fetal Circulation Syndrome / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control; D047928:Premature Birth; D018805:Sepsis / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D010431:Pentoxifylline
references.citation: Chest. 1993 Feb;103(2):565-75
references.pmid: 8432155
references.citation: Angiology. 1984 Jul;35(7):407-17
references.pmid: 6380349
references.citation: Pediatrics. 2008 Sep;122(3):491-9
references.pmid: 18762517
references.citation: Pediatrics. 2002 Aug;110(2 Pt 1):285-91
references.pmid: 12165580
references.citation: Recent Pat CNS Drug Discov. 2008 Nov;3(3):209-15
references.pmid: 18991810
references.citation: Pediatrics. 2001 Jan;107(1):E1
references.pmid: 11134465
references.citation: Neonatology. 2008;94(3):203-10
references.pmid: 18832856
references.citation: N Engl J Med. 2007 Nov 8;357(19):1893-902
references.pmid: 17989382
references.citation: J Trauma. 2009 Jan;66(1):17-24; discussion 24-5
references.pmid: 19131801
references.citation: J Pediatr. 1990 Jun;116(6):960-4
references.pmid: 2348301
references.citation: Br J Haematol. 1993 Jan;83(1):130-7
references.pmid: 8435320
references.citation: Life Sci. 2009 Jan 2;84(1-2):18-22
references.pmid: 18992758
references.citation: Eur J Pediatr. 1999 Jul;158(7):607
references.pmid: 10412826
references.citation: J Matern Fetal Neonatal Med. 2006 Jul;19(7):433-8
references.pmid: 16923699
references.citation: Crit Care Med. 1996 Jun;24(6):1072-8
references.pmid: 8681576
references.citation: Eur J Pediatr. 1994 Sep;153(9):663-7
references.pmid: 7957426
references.citation: Med J Malaysia. 2004 Aug;59(3):391-4
references.pmid: 15727386
references.citation: Semin Neonatol. 2003 Feb;8(1):29-38
references.pmid: 12667828
references.citation: Crit Care Med. 1999 Apr;27(4):807-14
references.pmid: 10321674
references.citation: Eur J Pediatr. 1996 May;155(5):404-9
references.pmid: 8741040
references.citation: Pediatr Res. 2006 Aug;60(2):185-9
references.pmid: 16864701
references.citation: Pediatr Res. 2004 Dec;56(6):901-6
references.pmid: 15470201
references.citation: Eur J Pharmacol. 2006 Mar 27;535(1-3):301-9
references.pmid: 16545799
references.citation: Arch Pediatr Adolesc Med. 2007 Jun;161(6):583-90
references.pmid: 17548764
references.citation: BMC Pediatr. 2007 Sep 05;7:30
references.pmid: 17784966
references.citation: Eur J Pediatr. 1993 May;152(5):460
references.pmid: 8319723
references.citation: J Am Acad Dermatol. 1994 Apr;30(4):639-42
references.pmid: 8157792
references.citation: Paediatr Drugs. 2006;8(3):179-88
references.pmid: 16774297
references.citation: Respiration. 1990;57(1):45-50
references.pmid: 2359896
references.citation: Drugs. 1987 Jul;34(1):50-97
references.pmid: 3308412
references.citation: Eur J Pediatr. 1994 Sep;153(9):672-4
references.pmid: 7957428
references.citation: Biol Neonate. 2004;86(1):29-33
references.pmid: 15017117
references.citation: Angiology. 1985 Jun;36(6):387-98
references.pmid: 3927788
references.citation: N Engl J Med. 2006 May 18;354(20):2112-21
references.pmid: 16707748
references.citation: Eur J Pharmacol. 2008 Mar 10;581(3):290-5
references.pmid: 18155691
references.citation: Am J Pathol. 1987 Nov;129(2):217-22
references.pmid: 3674202
references.citation: Crit Care Med. 1996 Jun;24(6):940-6
references.pmid: 8681595