(R)-2-(3-mercapto-2(S)-methyl-1-oxo-propoxy)-3-(methylthio)propanoic acid, the first ultra-short-acting angiotensin converting enzyme inhibitor.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
R D Carr
Publications and source records attributed to R D Carr.
Antianxiety properties of the angiotensin II antagonist, DUP 753, in the rat using the elevated plus-maze.
The angiotensin II receptor antagonist, DUP 753 (Losartan), was compared with diazepam for antianxiety properties in the rat using the elevated plus-maze. Oral diazepam (5 mg kg-1) resulted in a significantly greater number of entries of rats into the open arms of the maze, an increase in time spent in the open arms and a decreased time spent in the closed arms. Oral doses of DUP 753 likewise resulted in significantly greater numbers of entries into the open arms (active at 0.0001, 0.001, 0.01 and 0.1 mg kg-1), increased time spent on the open arms (active at 0.0001-0.01 mg kg-1) and a decreased time spent in the closed arms (active at 0.0001, 0.01 and 0.1 mg kg-1). Larger (1.0 mg kg-1) or smaller (0.00001 mg kg-1) doses of DUP 753 were not active.
Angiotensin II↗
Coronary vasoconstriction in the conscious rabbit following intravenous infusion of L-NG-nitro-arginine.
Intravenous infusion of L-NG-nitro-arginine, an inhibitor of endothelial nitric oxide (NO) synthesis, produced vasoconstriction in the coronary, cerebral, renal and duodenal vascular beds of the conscious rabbit. In this study, using radiolabelled microspheres, we provide in vivo evidence for a basal NO-dependent vasodilator tone in the coronary vascular bed.
Animals↗
Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin-converting enzyme.
1. FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotension converting enzyme (ACE) in vitro (IC50 0.51 nM). 2. In conscious normotensive dogs, FPL 63547 (10-300 micrograms kg-1 i.v.) produced prolonged, dose-related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. 3. In anaesthetized dogs, FPL 63547 diacid (3-300 micrograms kg-1 i.v. cumulatively) produced dose-related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. 4. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 X 10(-7)-10(-5) mol kg-1 p.o. (congruent to 0.13-4.5 mg kg-1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10(-6), 10(-6) and 3 X 10(-5) mol kg-1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. 5. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg-1 day-1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre- and post-dose, i.e. effective 24 h control had been achieved. 6. The profile of FPL 63547 is consistent with it being a potent, selective and long-acting ACE inhibitor. As an antihypertensive agent in SHR it compared favourably with other members of this class with respect to potency and duration of action.
Angiotensin I↗
Preferential biliary elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme, in the rat.
1. The route of elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme (ACE), has been investigated in the anaesthetized rat. Comparisons have been made with other ACE inhibitors. 2. Bile and urine samples were collected over a 5 hour period following a single i.v. dose of ACE inhibitor (2 mumol kg-1). Samples were bioassayed for ACE inhibitory activity using affinity-purified rabbit lung ACE and the amounts of the active form of inhibitor present in each sample were calculated by comparison with a standard curve. 3. FPL 63547 was rapidly and extensively excreted as the diacid in the bile but appeared in the urine in negligible amounts. The bile:urine ratio was 21.4:1 indicating a marked preference for the biliary route. A similar elimination profile was observed when the compound was dosed in its active form (FPL 63547 diacid), 87.9% of which was found in the bile over the 5 h collection period, with a bile: urine ratio of 14.6:1. 4. The marked preference of FPL 63547 for biliary elimination was not shared by the other ACE inhibitors tested in this study. Lisinopril demonstrated the opposite pattern, being excreted almost exclusively by the kidney (bile:urine ratio 0.06:1). Enalapril was eliminated in approximately equal amounts in bile and urine (ratio 0.7:1) while spirapril diacid showed a slight preference for the bile (ratio 2.6:1). 5. The physical chemical properties of FPL 63547 diacid may be responsible for its unusual preference for biliary elimination. In particular, the amphipathic character and strong acid functionality of the compound are thought to favour transport into the bile. 6. Elimination by the biliary route will be preferred in patients whose renal function is impaired as a result of disease or age. In such patients the elimination of renally-excreted ACE inhibitors is known to be compromised, resulting in compound accumulation and the need for closer monitoring. Therefore, the elimination profile of FPL 63547, if confirmed in man, may prove to be clinically advantageous.
Anesthesia↗
Clinical evaluation of a polymeric membrane dressing in the treatment of pressure ulcers.
The healing effects of the Ferris polymeric membrane dressing were tested in a 70-day evaluation of 18 ulcers on 13 elderly subjects with Stage I, II, and III pressure ulcers. The mean length of time these ulcers had been present prior to the trial dressing was 144 days with 50% of the ulcers (n = 9) present for 75 days or longer. Over 60% of the ulcers were completely healed and over 94% were improved during the study.
Aged↗
Progressive cribriform and zosteriform hyperpigmentation.
Five cases of progressive cribriform and zosteriform hyperpigmentation are described. The following criteria were fulfilled: (1) uniformly tan cribriform macular pigmentation in a zosteriform distribution; (2) a histologic pattern that consisted of a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells; (3) no history of rash, injury, or inflammation to suggest postinflammatory hyperpigmentation; (4) onset well after birth with gradual extension; and (5) lack of other associated cutaneous or internal abnormalities. This appears to be a newly described entity, although it resembles a Becker's nevus without hypertrichosis or an typical café au lait spot. We believe that such progressive cribriform and zosteriform pigmentation is not uncommon.
Adolescent↗