title: Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies.
abstract: BACKGROUND
  We evaluated the clinical effectiveness of variable courses of paracetamol on patent ductus arteriosus (PDA) closure and examined its effect on the in vitro term and preterm murine ductus arteriosus (DA).
  
  
  METHODS
  Neonates received one of the following three paracetamol regimens: short course of oral paracetamol (SCOP), long course of oral paracetamol (LCOP), and intravenous paracetamol (IVP) for 2-6 d. Pressure myography was used to examine changes in vasomotor tone of the preterm and term mouse DA in response to paracetamol or indomethacin. Their effect on prostaglandin synthesis by DA explants was measured by mass spectroscopy.
  
  
  RESULTS
  Twenty-one preterm infants were included. No changes in PDA hemodynamics were seen in SCOP infants (n = 5). The PDA became less significant and eventually closed in six LCOP infants (n = 7). PDA closure was achieved in eight IVP infants (n = 9). On pressure myograph, paracetamol induced a concentration-dependent constriction of the term mouse DA, up to 30% of baseline (P < 0.01), but required >1 µmol/l. Indomethacin induced greater DA constriction and suppression of prostaglandin synthesis (P < 0.05).
  
  
  CONCLUSIONS
  The clinical efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration. Paracetamol is less potent than indomethacin for constriction of the mouse DA in vitro.
authors.affiliation: Department of Pediatrics, The Rotunda Hospital, Dublin, Ireland.
authors.forename: Afif
authors.initials: A
authors.lastname: El-Khuffash
authors.affiliation: Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Amish
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Pediatrics, The Rotunda Hospital, Dublin, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Corcoran
authors.affiliation: Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Prakesh S
authors.initials: PS
authors.lastname: Shah
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Hooper
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Naoko
authors.initials: N
authors.lastname: Brown
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Poole
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Shelton
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Jeff
authors.initials: J
authors.lastname: Reese
authors.affiliation: 1] Department of Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage*; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D004374:Ductus Arteriosus, Patent / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007231:Infant, Newborn; D008026:Ligation; D011448:Prostaglandin Antagonists / Q000008:administration & dosage*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D011448:Prostaglandin Antagonists; D014662:Vasoconstrictor Agents; D000082:Acetaminophen; D007213:Indomethacin