Rm. Angus et al., NO EFFECT OF THE ORAL NEUTRAL ENDOPEPTIDASE INHIBITOR CANDOXATRIL, ONBRONCHOMOTOR TONE AND HISTAMINE REACTIVITY IN ASTHMA, The European respiratory journal, 7(6), 1994, pp. 1084-1089
Neutral endopeptidase (NEP) is found in many tissues in man, including
the lung. Metabolism by NEP is one of the main mechanisms for the cle
arance of atrial natriuretic peptide (ANP), a hormone that causes bron
chodilation and reduces nonspecific bronchial reactivity in man. Cando
xatril, an oral NEP inhibitor has been shown to elevate circulating AN
P levels. We have sought to determine whether the administration of ca
ndoxatril will alter bronchomotor tone (forced expiratory volume in on
e second (FEV1)) and histamine reactivity. Ten male asthmatic patients
with stable asthma were enrolled (mean (SD) age 32 (10) yrs; FEV1 92
(11) % predicted) in a randomized, double-blind, placebo-controlled st
udy. On each study day, after baseline spirometry, patients received 2
00 mg of candoxatril or placebo. Spirometry was repeated at half hourl
y intervals. After 2 h a histamine inhalation test was performed. Ther
e was no significant difference in FEV1 values at baseline or at 2 h p
ost-dosing between active and placebo study days, with mean (SEM) FEV1
at baseline and 2 h of 3.71(0.29) l and 3.85(0.29) l on the placebo d
ay, and 3.89(0.27) l and 4.05(0.82) l on the active day, respectively.
The geometric mean (range) provocative concentration of histamine pro
ducing a 20% fall in FEV1 (PC20) on the placebo day and active day did
not differ significantly, being 1.17(0.25-25.8) and 0.93(0.13-32) mg.
ml-1, respectively. ANP levels rose significantly on the active day, f
rom a mean (SEM) baseline value of 12.1 (2.1) pg.ml-1 to 29.1(4.8) pg.
ml-1 at 2 h, but did not change on the placebo day (baseline 11.54(2)
pg.ml.1 and 2 h level 10.8(1.9) pg.ml-1. Plasma drug levels were maxim
ally elevated between 2 and 3 h mean (SEM) plasma candoxatril at 1 h 1
61(53), 2 h 846(136), 3 h 896(68) and 4 h 626(60) ng.ml-1. No side-eff
ects were observed or noted by the patients. We conclude that the acut
e administration of the oral NEP inhibitor, candoxatril, does not alte
r bronchomotor tone or bronchial reactivity to histamine in stable ast
hmatic patients. This neutral effect of candoxatril is reassuring, and
permits further exploration of NEP inhibitors in the treatment of e.g
. cardiac failure.