NO EFFECT OF THE ORAL NEUTRAL ENDOPEPTIDASE INHIBITOR CANDOXATRIL, ONBRONCHOMOTOR TONE AND HISTAMINE REACTIVITY IN ASTHMA

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.