Disease relevance of UK 79300

• CONCLUSIONS: Candoxatril in a single dose caused no adverse effects in essential hypertension [1].
• CCT is an analogue of both candoxatrilat, a potent inhibitor of neutral endopeptidase 24.11, and of the 5-indanyl ester prodrug candoxatril, which is under clinical evaluation as a potential therapy for congestive heart failure [2].
• Four weeks after myocardial infarction, B(2)-/- mice and B(2)+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks [3].
• The effects of candoxatril on hemodynamic parameters and cardiovascular hypertrophy were evaluated in the rat model of myocardial infarction [4].
• These data indicate that inhibition of neutral endopeptidase by candoxatril at a dose of 10 mg/kg per day did not oppose cardiac hypertrophy in the rat model of myocardial infarction in spite of significant neutral endopeptidase inhibition [4].

High impact information on UK 79300

• When candoxatril was co-administered with valine pyrrolidide (a DPP-IV inhibitor), changes in C-terminal GLP-1 pharmacokinetics mirrored those seen when candoxatril alone was administered (t(1/2) 2.7+/-0.3 and 7.7+/-0.8 min; MCR 17.3+/-2.6 and 6.5+/-0.8 ml.kg(-1).min(-1) for valine pyrrolidide without and with candoxatril, respectively) [5].
• METHODS: The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs [5].
• BACKGROUND: Candoxatril is an atriopeptidase inhibitor [6].
• Frusemide significantly increased mean plasma renin activity (days 0 and 42), and the mean aldosterone concentration (day 42) in comparison with placebo, whereas candoxatril caused no significant changes in any of the hormonal parameters assessed [6].
• Only candoxatril significantly reduced pulmonary capillary wedge pressure during exercise on day 0, while both drugs significantly reduced this parameter on day 42 [6].

Chemical compound and disease context of UK 79300

• Daily administration of SA7060, candoxatril or enalapril significantly suppressed the development of hypertension induced by DOCA and salt, although the effect of enalapril was less potent at 4-weeks of the treatment period [7].

Biological context of UK 79300

• There was a trend for a small reduction in blood pressure in the candoxatril group [8].
• Candoxatril significantly further augmented natriuresis in group 2 (P less than 0.01), but not group 1 [9].
• Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin [10].
• Individually, both 50 mg and 200 mg but not 10 mg candoxatril significantly altered the elimination kinetics of ANP [11].
• A significant natriuresis was only seen after 200 mg candoxatril, with a greater cumulative urine sodium excretion over 12 h compared with placebo; this was associated with a greater diuresis over 12 h compared with placebo [1].

Anatomical context of UK 79300

• The aim of the study was to investigate the haemodynamic and endocrine effects of the NEP inhibitor candoxatril in patients with congestive heart failure (CHF) [12].
• Myocardial infarction was induced by left coronary artery ligation in rats and they were treated either with candoxatril (10mg/kg per day) or a vehicle for up to 4 weeks [4].

Associations of UK 79300 with other chemical compounds

• AIMS: To assess the effect of candoxatril, a novel neutral endopeptidase inhibitor, on exercise capacity, clinical status and quality of life in patients with mild to moderate chronic heart failure receiving angiotensin converting enzyme inhibition [8].
• RESULTS: Candoxatril decreased blood pressure and increased urinary sodium excretion, both of which were greater in DOCA-salt rats than in normotensive control rats [13].
• Pretreatment with a specific ANP receptor antagonist (HS-142-1) diminished the effect of candoxatril on urinary sodium excretion, blood pressure and urinary cyclic GMP excretion [13].
• AIMS: To compare the effects on exercise capacity of the neutral endopeptidase inhibitor candoxatril, and the angiotensin converting enzyme inhibitor captopril, in patients with mild to moderate heart failure [14].
• Formation and pharmacokinetics of the active drug candoxatrilat in mouse, rat, rabbit, dog and man following administration of the prodrug candoxatril [15].

Gene context of UK 79300

• There is increasing evidence that NEP inhibitors such as candoxatril, expected to exhibit vasodilatory activity at least at certain doses and in certain clinical settings, even induce vasoconstriction [16].
• Therefore, the influence of candoxatril, a selective NEP inhibitor, on plasma levels of endogenous and exogenous glucagon was examined in anesthetized pigs [17].
• Although 4 days of pretreatment with the endopeptidase inhibitor did not affect basal plasma ANF, candoxatril enhanced mean ANF-induced increases in plasma ANF by 27 pmol/L (P = NS) and 42 pmol/L (P less than 0.002) in groups 1 and 2, respectively [9].
• These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril [10].
• Urinary ANP excretion also increased, but urinary BNP excretion was not changed by candoxatril [13].

Analytical, diagnostic and therapeutic context of UK 79300

• Following a 4-week single-blind placebo 'run-in' phase of weekly exercise tests, patients underwent double-blind randomization to receive either candoxatril (100 mg twice daily) or placebo for the next 84 days [8].
• Subjects were studied in a random order, single-blind study on two occasions, each 48 hours in length, when they were given UK 79300 (25 or 50 mg p.o.) or placebo at 12-hour intervals (each agent for 24 hours) [18].
• The renal, hormonal and haemodynamic effects of chronic (4 days) dosing with an inhibitor of endopeptidase EC 3.4.24.11 (UK 79300) were assessed in two groups, each of eight normal volunteers, receiving 25 mg every 12 h (group 1) or 100 mg every 12 h (group 2) of UK 79300 in double-blind, balanced-randomized, placebo-controlled, crossover studies [19].
• Before and 90 min after oral administration of UK 79300 or placebo aortic input impedance was assessed to characterize left ventricular hydraulic load [20].
• After candoxatril treatment there were reductions in PRA, especially on the low sodium diet [21].

References