A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics.
The inducible isoenzyme of nitric oxide synthase (iNOS) generates nitric oxide (NO) in inflammatory diseases such as asthma. The prodrug L-N6-(1-iminoethyl)lysine 5-tetrazole amide (SC-51) is rapidly converted in vivo to the active metabolite L-N6-(1-iminoethyl)lysine (L-NIL). Initially, we performed in vitro experiments in human primary airway epithelial cells to demonstrate that L-NIL causes inhibition of iNOS. In a randomized double-blind placebo-controlled crossover trial, SC-51 was administered as a single oral dose (20 or 200 mg) in separate cohorts of healthy volunteers (two groups of n=12) and mild asthmatic patients (two groups of n=12). SC-51 (200 mg) reduced exhaled breath NO levels to <2 ppb in both healthy volunteers (P<0.001) and mild asthmatics (P<0.001) within 15 min, representing >90% inhibition of baseline levels of NO in asthmatic patients, with the effects lasting at least 72 h. There were no significant effects on blood pressure, pulse rate, or respiratory function (FEV1). This study demonstrates that an inhibitor of iNOS produces marked inhibition of exhaled breath NO in normal and asthmatic subjects without producing the side effects observed following the systemic administration of non-selective NOS inhibitors, and thus provides support for the potential use of iNOS inhibitors to treat a range of inflammatory clinical disorders.
Hansel
Trevor T
TT
Clinical Studies Unit, National Heart and Lung Institute (NHLI), Imperial College, London, UK. t.hansel@ic.ac.uk
Kharitonov
Sergei A
SA
Donnelly
Louise E
LE
Erin
Edward M
EM
Currie
Mark G
MG
Moore
William M
WM
Manning
Pamela T
PT
Recker
David P
DP
Barnes
Peter J
PJ
D000284:Administration, Oral; D000328:Adult; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D001944:Breath Tests; D002478:Cells, Cultured; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006709:Homoarginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000032:analysis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology
D004791:Enzyme Inhibitors; C446200:L-N(6)-(1-iminoethyl)lysine tetrazole-amide; C090663:N(6)-(1-iminoethyl)lysine; D011355:Prodrugs; D006709:Homoarginine; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D008239:Lysine