Acute safety and effects on mucociliary clearance of aerosolized uridine 5'-triphosphate +/- amiloride in normal human adults.
Impaired mucociliary clearance contributes to the pathophysiology of several airways diseases including cystic fibrosis, asthma, and chronic bronchitis. Extracellular triphosphate nucleotides (adenosine 5'-triphosphate [ATP], uridine 5'-triphosphate [UTP]) activate several components of the mucociliary escalator, suggesting they may have potential as therapeutic agents for airways diseases. We conducted initial (Phase I) studies of acute safety and efficacy of aerosolized UTP alone and in combination with aerosolized amiloride, the sodium channel blocker, in normal human volunteers. Safety was assessed by measurement of pulmonary function. Neither UTP alone nor in combination with amiloride caused any clinically significant adverse effects on airway mechanics, (subdivisions of) lung volumes, or gas exchange. Acute efficacy of UTP and amiloride alone and in combination, was assessed by measuring changes in the clearance of inhaled radiolabeled particles. A 2.5-fold increase in mucociliary clearance was seen in response to UTP alone and in combination with amiloride. We conclude that aerosolized UTP +/- amiloride clearly enhances mucociliary clearance without acute adverse effects in normal adults, and may have therapeutic potential to enhance airways clearance in diseases characterized by retained airways secretions.
Olivier
K N
KN
Department of Medicine, University of North Carolina, Chapel Hill 27599-7020, USA.
Bennett
W D
WD
Hohneker
K W
KW
Zeman
K L
KL
Edwards
L J
LJ
Boucher
R C
RC
Knowles
M R
MR
D000328:Adult; D000336:Aerosols; D000584:Amiloride / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008450:Maximal Midexpiratory Flow Rate / Q000187:drug effects; D009079:Mucociliary Clearance / Q000187:drug effects*; D026941:Sodium Channel Blockers; D014544:Uridine Triphosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D014797:Vital Capacity / Q000187:drug effects
D000336:Aerosols; D026941:Sodium Channel Blockers; D000584:Amiloride; D014544:Uridine Triphosphate