Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system plays an important role in the regulation of blood pressure and fluid and electrolyte homeostasis. Components of this system, renin, angiotensin converting enzyme (ACE) angiotensinogen, angiotensin II and angiotensin II receptors have been found in many tissues including kidney, adrenal, blood vessels and in discrete brain regions. This suggests that in addition to circulating angiotensin II, endogenous tissue renin-angiotensin system may also be important in cardiovascular control and maintaining fluid balance. Inhibitors for ACE are used successfully in the treatment of hypertension and chronic heart failure. In experimental animals, these inhibitors are found to block ACE in the kidney, lung, adrenal, blood vessels and the forebrain circumventricular organs after oral administration. The time course of tissue ACE inhibition correlated closely with the blood pressure lowering effect of these drugs. Most ACE inhibitors are unable to penetrate the blood-brain and blood-testis barriers. However, the more lipophilic drugs do penetrate the blood brain barrier, especially after chronic administration. The potential use of inhibitors for renin and angiotensin II receptors for the treatment of hypertension are being explored. An inhibitor for the AT1 angiotensin receptor, losartan (CAS 124750-99-8), which has potent antihypertensive effect, demonstrated dose and time dependent inhibition of AT1 receptors in the kidney and adrenal. Losartan also crossed the blood-brain barrier after acute peripheral administration suggesting additional possible central sites of action.
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PMID:Localization of components of the renin-angiotensin system and site of action of inhibitors. 849 67

Drug induced modification of the renin-angiotensin system is of established benefit in the treatment of hypertension and heart failure. The responses to the angiotensin converting enzyme (ACE) inhibitor enalapril (CAS 75847-73-3) have been studied in essential hypertension and normotensive controls. The kinetics and dynamics of enalapril have been characterised in an integrated concentration-effect model to identify factors underlying responsiveness to the ACE inhibitor. In addition models to predict the response to long-term treatment from changes after the first dose have been developed. Enalapril response could be described by a non linear (Emax) model defined by two parameters - the maximum response (Emax) and the drug concentration required to cause 50% of the maximum response (C50). Acute dosing accurately predicted the Emax after 6 weeks treatment. In addition to individual pharmacokinetics, pretreatment blood pressure was the most important determinant of response to enalapril. In caucasian salt-replete essential hypertension neither age nor plasma renin activity were major factors. However, in states of sodium restriction and/or diuretic treatment, the response to enalapril was greatly increased. The angiotensin II receptor antagonist, losartan has been reported to be without effect on blood pressure in salt-replete normals. Salt restriction together with furosemide for 3 days led to dose-related falls in blood pressure in normal subjects after losartan 25-100 mg. Concentration-effect analysis can be used to describe blood pressure responses, to predict the responses to long-term treatment and also to identify quantitatively important factors determining the response in individual patients.
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PMID:Inhibitors of the renin-angiotensin system. Clinical pharmacology studies on kinetics, dynamics and concentration-effect relationships. 849 75

The effects of the diuretic furosemide (CAS 54-31-9) 1 mg/kg bw i.v., of the angiotensin converting enzyme (ACE) inhibitor captopril (CAS 62571-86-2) 1 mg/kg bw p.o. and the prostaglandin synthesis inhibitor indometacin (CAS 53-86-1) 2 mg/kg bw p.o. on kidney function, salt and water excretion, the excretion of renal prostaglandins PGE2, PGF2a, 6-keto-PGF1a, thromboxane B2 (TXB2) and the plasma renin activity (PRA) were investigated on 29 neonatal piglets. Within 1 h, fuorsemide led to pronounced diuresis and natriuresis, to a rise of the glomerular filtration rate (GFR) (which ist low in neonatal pigs) by 1.8 times, increased the excretion of renal prostaglandins (especially the vasoconstrictor, thromboxane B2 (TXB2 and PGF2a) and raised the PRA significantly. Under captopril, the PRA rose significantly, whereas there was no unequivocal change in the excretion of renal prostaglandins. There was a pronounced decline of the sodium and potassium excretion in the urine with a fall in the concentrations of electrolytes in serum and of the hematocrit. Under indometacin, the excretion of all prostaglandins in the urine declined (this decline was most pronounced for PGE2). There was also a decrease in sodium excretion, whereas there was no significant change in PRA. It can be concluded from the results that the effects of the investigated drugs on the pig neonate kidney is at least partially attributable to an influence on hormonal factors.
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PMID:Effects of furosemide, captopril and indometacin on the renin-angiotensin system and the renal prostaglandins in anesthetized neonatal piglets. 857 31

The pharmacodynamic and toxicological profile of the new angiotensin converting enzyme (ACE) inhibitor moexipril (CAS 82586-52-5) and its active diacid metabolite moexiprilat were studied in vitro as well as in vivo. In vitro, moexiprilat was a potent inhibitor of ACE in guinea pig serum as well as on purified ACE from rabbit lung with IC50 values of 2.6 and 4.9 nmol/l, respectively. Both, moexipril and moexiprilat inhibited the angiotensin I (ANG I)-induced contractions of rabbit aorta concentration-dependently, whereas contractions by other agents were not affected, indicating a high selectivity of both compounds for ACE. Similar results were obtained in vivo in experiments investigating the blood pressure increasing response to intravenous injection of ANG I or ANG II in conscious normotensive rats and dogs after oral or intravenous application of moexipril or moexiprilat, respectively. The antihypertensive effects of the oral application of moexipril were studied in models of hypertension in the rat as well as in renal hypertensive dogs. In renal hypertensive rats, moexipril (0.03-10 mg/kg p.o.) caused a dose-dependent decrease in blood pressure with a threshold dose of 0.3 mg/kg. Once daily treatment of the animals with 3 mg/kg/d for 5 days lowered mean blood pressure by about 70 mmHg and blood pressure was maintained on this low level for the experimental period. In spontaneously hypertensive rats, oral administration of moexipril (30 mg/kg/d) for 5 days caused a progressive lowering of mean blood pressure from pre-treatment values of 180 +/- 7 mmHg to a trough on day 4 of 127 +/- 4 mmHg. In perinephritic hypertensive dogs, oral administration of moexipril (10 mg/kg) in combination with hydrochlorothiazide (10 mg/kg) caused a drop of mean blood pressure by 25 mmHg from pre-treatment control, which persisted for 24 h. In all these models, the action was characterized by a rapid onset and a long duration of action. After cessation of treatment, a gradual return to baseline values was observed. In contrast, only slight blood pressure lowering effects were seen in normotensive rats at high doses (100 mg/kg p.o.). The general pharmacological properties of moexipril were also studied in generally accepted models in vitro and in vivo. In doses or concentrations more than 100 times higher than those causing ACE inhibition, no effects were observed on the central nervous system, on isolated smooth muscle preparations, the digestive system, the kidney or the lung. Additionally, moexipril is devoid of anti-inflammatory properties and has no effect on platelet function. On the cardiovascular system, the effects observed can be attributed to ACE inhibition by moexipril. Repeated dose toxicity studies in rats and dogs revealed the heart and kidneys as target organs. These effects, based on highly exaggerated pharmacological activity, are comparable to other ACE-inhibitors. No potential for mutagenic or carcinogenic activity and no evidence of reproductive toxicity was apparent for meoxipril. The preclinical data indicate that moexipril possesses a high degree of specifity as an ACE-inhibitor without relevant side effects or gross toxicity.
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PMID:Pharmacological and toxicological studies of the new angiotensin converting enzyme inhibitor moexipril hydrochloride. 907 32

The general pharmacological properties of a combination of the angiotensin converting enzyme (ACE) inhibitor moexipril hydrochloride (CAS 82586-52-5) and the thiazide diuretic hydrochlorothiazide (CAS 58-93-5, HCTZ), ratio 7.5 + 12.5, were studied in generally accepted models in vitro and in vivo. In vitro, the combination showed neither agonistic nor antagonistic activities on the isolated guinea pig trachea in concentrations up to 2 x 10(-4) g/ml. In mice, there was no effect on intestinal motility or the thiopental-induced sleeping time up to 1000 mg/kg. The only activity observed in mice was an inhibition of spontaneous motility after oral dosing with 300 and 1000 mg/kg, respectively. Both HCTZ (1-10 mg/kg) alone and the combination moexipril/HCTZ (1.6 or 4.8 mg/kg) produced dose-related increases in diuresis and electrolyte excretion in rats, however, without any potentiating effects for the drug combination. On the cardiovascular system of anaesthetised dogs, the effects observed were as expected, e.g. dose-related decrease in blood pressure. Repeated dose toxicity studies in rats and dogs revealed the kidney as target organ. This effect, based on highly exaggerated pharmacological activity, is well-known for other ACE inhibitors. No potential for teratogenic effects could be observed for the drug combination. In summary, the preclinical data indicate that the combination of moexipril and HCTZ (ratio 7.5 + 12.5) represents a safe drug without relevant side effects or gross toxicity.
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PMID:Preclinical safety studies of the combination moexipril hydrochloride/hydrochlorothiazide. 960 78

This study was carried out to investigate the pharmacokinetics of zofenopril (CAS 81938-43-4) and zofenoprilat, the behaviour of the angiotensin converting enzyme (ACE) (pharmacodynamics) following the administration of zofenopril calcium at the single oral dose of 60 mg in eighteen healthy volunteers. This open label, one-way study was carried out in a single centre on 18 healthy volunteers. The volunteers received an oral single 60 mg dose of zofenopril calcium following an overnight fast. The tablet was swallowed with 250 ml of water. Fasting continued for additional 4 h after dosing and no other liquid intake was allowed from 1 h before to 2 h after administration. Plasma concentrations of zofenopril and its active metabolite zofenoprilat as well as serum ACE activity were measured before drug intake (baseline) and on timed samples over a 36 h period after dosing by LC-MS-MS, a highly sensitive, validated method for active moiety concentrations. Peak plasma concentration was reached on average at 1.19 h with zofenopril and at 1.36 h with zofenoprilat. Concentrations then decreased reaching values under or close to the limit of quantitation (1 ng.ml-1 for zofenopril, 2 ng.ml-1 for zofenoprilat) from 8 to 16 h after dosing. Complete inhibition of ACE was seen at the first blood sampling time (1 h) and lasted on average up to 9.44 h. ACE activity then slowly reactivated, but enzyme inhibition continued and was estimated to be 74% and 56% at 24 and 36 h following drug administration, respectively. From these data a complete or almost complete enzyme inhibition is expected with zofenopril given in repeated dose regimen.
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PMID:Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers. 1063 43

Endothelial function is impaired in hypertension. In the present study the effects of long-term antihypertensive therapy on endothelial production of nitric oxide (NO) were investigated. Fifteen untreated mild to moderate essential hypertensive patients and 13 normotensive subjects were enrolled in this study. Blood pressure, heart rate, lipid profiles, cyclic guanosine 3', 5'-monophosphate (cGMP) and nitrite/nitrate (NOx), which are stable metabolites of NO, were measured. The hypertensive patients were treated with a calcium antagonist, benidipine (CAS 91559-74-5) (Ca group: n = 8) or an angiotensin converting enzyme inhibitor, trandolapril (CAS 87679-37-6) (ACEI group: n = 7) and 12 weeks after the treatment the same examinations were performed. NOx and cGMP levels in hypertensive patients were significantly lower than those in normotensive subjects (32.3 +/- 4.1 versus 49.0 +/- 6.5 mumol/l and 2.16 +/- 0.39 versus 3.39 +/- 0.42 pmol/ml, respectively). Both antihypertensive agents decreased the elevated blood pressure (mean blood pressure; 120 +/- 3 to 99 +/- 3 mmHg in Ca group and 117 +/- 4 to 104 +/- 4 mmHg in ACEI group) and normalized the decreased NOx and cGMP levels (29.1 +/- 6.2 to 46.2 +/- 8.6 mumol/l and 1.96 +/- 0.37 to 3.20 +/- 0.71 pmol/ml in Ca group, 36.0 +/- 5.3 to 54.7 +/- 6.9 mumol/l and 2.45 +/- 0.52 to 2.87 +/- 0.43 pmol/ml in ACEI group, respectively). Either benidipine or trandolapril improves the endothelial function and increases the impaired basal release of NO in hypertension. This suggests the beneficial effects of the drugs on protection against the vascular complications in hypertension.
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PMID:Long-term effect of antihypertensive therapy with calcium antagonist or angiotensin converting enzyme inhibitor on serum nitrite/nitrate levels in human essential hypertension. 1091 45

Zofenopril calcium (CAS 81938-43-4) is a new angiotensin converting enzyme (ACE) inhibitor, which in addition to the typical activity of the class, proved to possess a specific cardioprotective effect due also to the presence of the sulfhydryl group. In this trial zofenopril calcium and enalapril maleate (CAS 76095-16-4) were given to 20 healthy volunteers of both sexes in repeated dose regiment at two dose levels: 30 mg and 60 mg zofenopril calcium and 10 mg and 20 mg enalapril maleate. The study was conducted according to a two-period, two-sequence, crossover design, with washout. ACE activity in serum and zofenopril, zofenoprilat, enalapril and enalaprilat plasma concentrations were determined during and on the last day of the two study periods. Both zofenopril and enalapril were extensively converted through hydrolysis to their active metabolites zofenoprilat and enalaprilat, respectively. Zofenopril exhibited a complete and a more rapid hydrolysis rate compared to enalapril, which is reflected by the higher metabolite to parent drug ratio of Cmax and AUCss, tau showed by this compound. Even though only two dose levels were investigated in this trial, the pharmacokinetics of both drugs seem to be linear. In line with previous trials, both compounds at both dose levels investigated produced complete or almost complete inhibition of ACE activity in serum, for a period lasting 6-8 h after administration, the inhibition being still relevant 24 h thereafter. The tolerability of the two drugs at both dose levels proved to be very good as demonstrated by subjective and objective symptoms, by the absence of relevant adverse events, and by laboratory biochemical parameters and vital signs evaluated before and after the trial. Blood pressure showed a fairly decreasing trend with both the drugs, systolic and diastolic blood pressure values being however within normal range in all the subjects. In no case symptoms of hypotension were experienced. In conclusion, zofenopril calcium and enalapril maleate show very good tolerability and appear to exert similar activity on serum ACE. The main difference in the pharmacokinetics of the two compounds is the conversion from pro-drug to the active metabolite which is faster with zofenopril.
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PMID:Pharmacokinetic and pharmacodynamic comparative study of zofenopril and enalapril in healthy volunteers. 1204 Sep 65

The purpose of this first prospective observational cohort study after launch was to document the efficacy and tolerability of therapy with the fixed combination of lercanidipine HCl (CAS 132866-11-6), a third-generation calcium antagonist, and the angiotensin converting enzyme (ACE) inhibitor enalapril maleate (CAS 76095-16-4) in patients with essential hypertension in daily practice. Both parts of the observational study were conducted with the fixed combination of enalapril maleate 10 respectively 20 mg and lercanidipine HCl 10 mg, one part with Zaneril and the other with Zanipress. The fixed combination is marketed under these product names in Germany. The data of 8,440 patients with a mean age of 62 years and a mean body mass index (BMI) of 28 kg/m2 were evaluated. 84% of the patients had already received pre-treatment for essential hypertension. 26% of all the patients were known to have had hypertension for at least 10 years. Around 70% had further concomitant diseases. The mean blood pressure before the beginning of the study was 162.5/ 94.5 mmHg, the mean reduction after around three months was 28.4/ 13.5 mmHg. Just under 80% of the patients reached the desired target blood pressure after the observation period. The global assessment of the physicians shows that the efficacy of the drugs was "very good" to "good" for 94% of the patients. Global tolerability was assessed as "very good" and "good" for 97% of the patients. Compliance was stated as "very good" and "good" for 97% of the patients. Adverse drug reactions were documented for 2% of all patients.
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PMID:Efficacy and tolerability of the fixed lercanidipine-enalapril combination in the treatment of patients with essential hypertension. 2042 43

To perform unconstrained face recognition robust to variations in illumination, pose and expression, this paper presents a new scheme to extract "Multi-Directional Multi-Level Dual-Cross Patterns" (MDML-DCPs) from face images. Specifically, the MDML-DCPs scheme exploits the first derivative of Gaussian operator to reduce the impact of differences in illumination and then computes the DCP feature at both the holistic and component levels. DCP is a novel face image descriptor inspired by the unique textural structure of human faces. It is computationally efficient and only doubles the cost of computing local binary patterns, yet is extremely robust to pose and expression variations. MDML-DCPs comprehensively yet efficiently encodes the invariant characteristics of a face image from multiple levels into patterns that are highly discriminative of inter-personal differences but robust to intra-personal variations. Experimental results on the FERET, CAS-PERL-R1, FRGC 2.0, and LFW databases indicate that DCP outperforms the state-of-the-art local descriptors (e.g., LBP, LTP, LPQ, POEM, tLBP, and LGXP) for both face identification and face verification tasks. More impressively, the best performance is achieved on the challenging LFW and FRGC 2.0 databases by deploying MDML-DCPs in a simple recognition scheme.
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PMID:Multi-Directional Multi-Level Dual-Cross Patterns for Robust Face Recognition. 2704 95


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