In vitro and in vivo inhibition of the 2 active sites of ACE by omapatrilat, a vasopeptidase inhibitor.

The vasopeptidase inhibitor omapatrilat inhibits both neutral endopeptidase and angiotensin-converting enzyme (ACE). The in vitro and in vivo inhibitory potency of omapatrilat and the specific ACE inhibitor fosinopril toward the 2 active sites of ACE (called N- and C-domains) was investigated with the use of 3 substrates: angiotensin I, which is equally cleaved by the 2 ACE domains; hippuryl-histidyl-leucine, specific synthetic substrate of the C-domain in high- salt conditions; and a newly synthesized specific substrate of the N-domain designed by acetylating the lysine residue of AcSDKP. In vitro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting angiotensin I hydrolysis. Omapatrilat inhibited similarly both N- and C-domain hydrolysis, whereas fosinoprilat was slightly more specific for the N-domain. The in vivo selective inhibitory potency of single oral doses of 10 mg omapatrilat and 20 mg fosinopril were investigated in a double-blind, placebo-controlled, cross-over study in 9 mildly sodium-depleted normotensive subjects. In accordance with the in vitro results, fosinopril appeared to be more specific for the N-domain than the C-domain in vivo, since plasma and urine AcSDKP concentrations were significantly higher than those observed with omapatrilat. This study shows that it is possible to assess separately in vitro and in vivo the selectivity of ACE or ACE/neutral endopeptidase inhibitors. A differential selectivity may explain some peculiar properties observed with some ACE inhibitors.

Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects.

Dehydroepiandrosterone (DHEA; 50 and 25 mg) and placebo tablets were orally administered daily to 24 healthy aging men and women (67.8 +/- 4.3 yr) for 8 days according to a balanced incomplete block design. Nine blood tests on both the first and eighth days allowed the measurement of DHEA, its sulfate DHEAS, and metabolites: testosterone, 5alpha-androstan-3alpha,17beta-diol glucuronide, estradiol, and estrone. Relatively low background levels of DHEA(S) were observed, and with the reestablishment of "young" levels, four important results were obtained. 1) Blood DHEA had an apparent terminal half-life of more than 20 h, the same order of magnitude as that of blood DHEAS, a result explainable by back-hydrolysis of the large amount of DHEAS formed after oral administration of DHEA, a mechanism providing long-lived unconjugated DHEA and metabolites. 2) The metabolic conversion of DHEAS to DHEA was significantly greater in women than in men. 3) No accumulation of steroids was observed. 4) No worrying transformation to androgen and estrogen was recorded; indeed, the limited increased estradiol in aged women could be predicted to be beneficial. These results suggested that daily oral administration of DHEA (25/50 mg) is safe in elderly subjects. The 50-mg dose was chosen for a 1 yr, double blind, placebo-controlled trial of daily oral administration of DHEA in 60- to 80-yr-old individuals (DHEAge).

Pharmacodynamic effects of dual neutral endopeptidase-angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans.

BACKGROUND: There is currently no clear evidence that dual neutral endopeptidase-angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase-angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensin-converting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9+/-3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16+/-5 pg/mL) and placebo (16+/-5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2+/-1.3-fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898+/-333 pg x h x mL(-1)) and 20 mg fosinopril (4383+/-302 pg x h x mL(-1); difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79+/-84 mm Hg x h) only for 20 mg fosinopril (181+/-6 mm Hg x h; P < .05) but not for 10 mg BMS-186716 (118+/-7 mmHg x h). CONCLUSIONS: In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure-lowering effect than 20 mg fosinopril.

Comparing the effects of aspartame and sucrose on motivational ratings, taste preferences, and energy intakes in humans.

This study compared the effects of four breakfast preloads on motivational ratings, taste preferences, and energy intakes of 24 normal-weight nondieting young men and women. The preloads, composed of creamy white cheese (fromage blanc), were either plain or sweetened with aspartame or sucrose. Their energy value was either 1255 or 2929 kJ (300 or 700 kcal). Taste preferences were measured before and 150 min after breakfast. Motivational ratings were obtained at 30-min intervals. The subjects ate lunch, snack, and dinner meals in the laboratory. The consumption of low-energy as opposed to high-energy breakfasts, regardless of sweetness, led to elevated motivational ratings and increased energy intakes at lunch. However, intakes at subsequent meals were the same for all preloads, and no overall compensation in energy was observed. Aspartame did not promote hunger or lead to increased energy intakes in normal-weight subjects.

The effects of aspartame versus sucrose on motivational ratings, taste preferences, and energy intakes in obese and lean women.

This study examined the effects of four breakfast preloads of different sweetness and energy content on motivational ratings, taste preferences, and energy intakes of 12 obese and 12 lean women. The preloads consisted of creamy white cheese (fromage blanc) and were either plain, sweetened with sucrose or aspartame, or sweetened with aspartame and supplemented with maltodextrin. Their energy content was either 300 kcal (1,255 kJ) or 700 kcal (2,929 kJ). Motivational ratings of hunger and the desire to eat were obtained prior to and at 30 min intervals after breakfast. Taste preferences were measured prior to and 150 min after breakfast. The subjects ate buffet-style lunch, snack, and dinner meals in the laboratory. Obese women consumed significantly more energy at meals (2,596 kcal or 10,862 kJ) than did lean women (1,484 kcal or 6,209 kJ); derived a greater proportion of energy from fat (39.9% vs. 35.5%), and had lower dietary carbohydrate-to-fat ratios. Consumption of low-energy as opposed to high-energy breakfast preloads was associated with elevated motivational ratings by noon. However, energy intakes at lunch, snack, or dinner did not vary as a function of preload type, and no compensation was observed for the energy consumed at breakfast. Taste preferences were not affected by preload ingestion or by preload type. The study provided no evidence that aspartame promotes hunger or results in increased energy intakes in obese or in lean women.