title: Combined treatment with a nonselective nitric oxide synthase inhibitor (l-NMMA) and indomethacin increases ductus constriction in extremely premature newborns.
abstract: Studies in premature animals suggest that 1) prolonged tight constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [N(G)-monomethyl-L-arginine (L-NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and L-NMMA in newborns born at <28 weeks' gestation who had persistent ductus flow by Doppler after an initial three-dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h). Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h) plus a 72-hour L-NMMA infusion]. Thirty-eight newborns received three additional indomethacin doses (without L-NMMA) and served as a comparison group. Ninety-two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L-NMMA infusions were limited in dose and duration by acute side effects. Doses of 10-20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited L-NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at <28 weeks' gestation. However, the combined administration of L-NMMA and indomethacin was limited by acute side effects in this treatment protocol.
authors.affiliation: Department of Pediatrics, Cardiovascular Research Institute, Pharmacy, University of California San Francisco, CA 94143, USA. kellerr@peds.ucsf.edu
authors.forename: Roberta L
authors.initials: RL
authors.lastname: Keller
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Tacy
authors.forename: Scott
authors.initials: S
authors.lastname: Fields
authors.forename: John P
authors.initials: JP
authors.lastname: Ofenstein
authors.forename: Jacob V
authors.initials: JV
authors.lastname: Aranda
authors.forename: Ronald I
authors.initials: RI
authors.lastname: Clyman
mesh_terms: D004359:Drug Therapy, Combination; D004373:Ductus Arteriosus / Q000187:drug effects; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use*; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000188:drug therapy*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019323:omega-N-Methylarginine / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D007213:Indomethacin