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 angiotensin I-converting enzyme (CE) inhibitors, trandolapril (RU 44570) and enalapril were administered for 2 weeks to SHR at doses (3 and 10 mg/kg/day, p.o., respectively) that produced important and comparable inhibitions of plasma (84 and 88%), aorta (97 and 88%), and atrium (89 and 82%) CE activities. At these doses, the inhibitory effects of trandolapril and enalapril were nonetheless different on CE in heart ventricle (58 and 72%) and kidney (45 and 85%). In addition, although both drugs reduced blood pressure (BP) and heart hypertrophy, trandolapril was more potent despite a lower dose-ratio. All these parameters were reexamined 1, 3, and 8 days after drug withdrawal: BP returned to control levels within 3 days in enalapril-treated rats, whereas it remained low for at least 8 days in trandolapril-treated animals. The reduction of heart hypertrophy owing to trandolapril was still present 8 days after drug discontinuation. On cessation of treatment, plasma CE increased above controls, ventricle CE returned to control levels within 3 days, whereas atrial and aortic CE activities remained inhibited for 8 days in the enalapril group. In contrast, in trandolapril-treated rats, CE activities in serum and tissues were still inhibited after 8 days. These results demonstrate that at the doses used trandolapril is more potent and longer acting than enalapril.
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PMID:Cardiovascular actions and tissue-converting enzyme inhibitory effects of chronic enalapril and trandolapril treatment of spontaneously hypertensive rats. 247 5

A patient with congestive heart failure and mild renal impairment developed exfoliative dermatitis following the addition of captopril to her therapy. The skin reaction responded to drug withdrawal and the administration of corticosteroids, though the patient subsequently succumbed to the complications of an incidental myocardial infarction. Recognition and prompt treatment of this potentially fatal dermatological crisis is stressed. The newer generation of angiotensin converting enzyme inhibitors may have a lesser propensity for cutaneous complications.
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PMID:Captopril-related exfoliative dermatitis. 252 7

We describe the first case of de novo asthma following treatment with the angiotensin converting enzyme (ACE) inhibitor captopril. Despite drug withdrawal there was evidence of persistent airways obstruction and bronchial hyperreactivity. This suggests the possibility that ACE inhibitors may uncover an asthmatic tendency in patients with pre-existing bronchial hyperreactivity.
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PMID:Development of persistent late onset asthma following treatment with captopril. 266 36

The antihypertensive activity of spirapril given alone or in combination with felodipine was investigated in spontaneously hypertensive rats (SHR) during a 3-week treatment regimen and for one week after drug withdrawal. Systolic blood pressure and heart rate were recorded once a week just before dosing and at varying time intervals up to 6 hr thereafter. Recordings were continued for one week after drug withdrawal. Spirapril alone at 1 and 5 mg/kg p.o. was found to produce dose-related antihypertensive effects throughout the treatment period. Felodipine alone at 5 mg/kg p.o. reduced blood pressure slightly more than did the low dose of spirapril. The combination of spirapril and felodipine induced a marked antihypertensive response which was greater than that observed in rats treated with either drug alone. One week after treatment withdrawal, blood pressure was at initial levels with no evidence of rebound phenomena. No significant heart rate changes were observed in the treated groups, as compared with the controls, except for an increase on the 1st day of treatment in rats given felodipine. These findings indicate that the combination of an angiotensin converting enzyme (ACE) inhibitor with a calcium antagonist leads to an effective control of hypertension over a prolonged period of treatment. Since the combination allows effectiveness with lower doses of ACE inhibitor, it is expected that the antihypertensive efficacy might be associated with a lower liability to untoward effects.
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PMID:Antihypertensive effect of spirapril and felodipine during repeated administration to spontaneously hypertensive rats. 283 72

The antihypertensive activity of SCH 33844, a new angiotensin converting enzyme inhibitor, was investigated in conscious spontaneously hypertensive rats during a 3-week treatment regimen and for 1 week following drug withdrawal. SCH 33844 was given once daily at 2 dose levels (1 and 5 mg/kg orally) and its effects were compared with those of captopril (60 mg/kg orally). Systolic blood pressure was recorded twice weekly just before administration and at varying time intervals up to 6 hr after dosing; recordings were continued for 1 week after drug withdrawal. SCH 33844 was found to produce dose-related antihypertensive effects. Given at 1 mg/kg, the compound elicited small but significant blood pressure changes during the treatment. After drug withdrawal, systolic blood pressure returned to pre-drug levels within 1 week. SCH 33844 at 5 mg/kg, and captopril at 60 mg/kg, both reduced blood pressure markedly and to a similar extent. After each administration the effect was rapid in onset, lasted for over 6 hr and was not subject to tolerance. Drug withdrawal resulted in a gradual return of systolic blood pressure toward pre-treatment levels within 1 week, with no evidence of rebound phenomena. These results indicate that SCH 33844, like captopril, produces an effective antihypertensive action throughout a repeated dosing.
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PMID:Antihypertensive activity of a new ACE-inhibitor, SCH 33844, during repeated administration in spontaneously hypertensive rats. 303 29

Captopril (SQ 14225) is an inhibitor of angiotensin I-converting enzyme (ACE). Mice with schistosomiasis form granulomas in the liver and intestines that have high ACE activity. We determined whether chronic oral captopril administration would alter the granulomatous response. Infected mice treated with captopril had a dose-dependent decrease in liver granuloma size. Chronic peroral administration of drug induced a sustained decrease in granuloma ACE activity and size which was reversible upon drug withdrawal. The drug was most effective during the acute phase of infection. Granuloma size in the colon, ileum, and ileal Peyer's patches was also decreased by treatment. Ileal granulomas were affected the least. Liver, colon, ileum, and ileal Peyer's patches demonstrated natural differences in size of response to schistosome eggs. Synchronous hypersensitivity granulomas, containing no ACE activity, were generated by the pulmonary embolization of methylated bovine serum albumin-coated, Sepharose beads into sensitized mice. Captopril treatment did not affect the size of these lesions. Sustained improvements in portal pressure, body and liver weight, and water consumption were seen in treated mice. We conclude that captopril induces sustained suppression of the granulomatous response in schistosome-infected mice, which results in decreased morbidity. Circumstantial evidence suggests that captopril influences inflammation through the competitive inhibition of ACE.
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PMID:Alteration of the granulomatous response in murine schistosomiasis by the chronic administration of captopril, an inhibitor of angiotensin-converting enzyme. 626 48

Among the physicochemical, pharmacokinetic and pharmacodynamic properties that differentiate trandolapril from other angiotensin converting enzyme (ACE) inhibitors, the most clinically relevant ones are those that contribute to the long duration of action of the drug. The long elimination half-life of trandolapril and its strong lipophilicity, high ACE inhibitor potency and high affinity for the ACE cause the drug to have a long biological half-life. The long duration of action of trandolapril may be demonstrated experimentally; near total ACE inhibition is observed 24 hours after single dose administration and there is significant ACE inhibition 72 hours following drug withdrawal after long term therapy. We have analysed the duration of blood pressure lowering during long term therapy with commercially available ACE inhibitors in published studies using ambulatory blood pressure monitoring. On the basis of results from 19 studies undertaken in patients with mild to moderate hypertension, it was possible to reconstruct the curve of the magnitude of blood pressure changes against time. Mean trough: peak ratio calculations showed that once-daily administration produced ratios higher than 50% with enalapril (40 to 80%), lisinopril (40 to 70%) and trandolapril (50 to 100%). Other ACE inhibitors had trough: peak ratios lower than 50%. Despite many methodological limitations, this literature analysis demonstrates that trandolapril has a blood pressure-lowering effect for the full 24-hour period. Studies in which a dose is occasionally omitted show that the blood pressure-lowering effect of trandolapril may last beyond 24 hours.
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PMID:Trandolapril. How does it differ from other angiotensin converting enzyme inhibitors? 751 72

GUIDELINES ON DRUG SAFETY: Recent European Union draft guidelines for the safety evaluation of drugs intended for long-term use state that during drug development the safety profile of the new compound should be assessed over a period of time consistent with intended usage. This is in reasonable agreement with guidelines prepared by other regulatory authorities. CLINICAL DRUG DEVELOPMENT: Satisfactory preclinical data on a new compound are used to obtain authorization for human testing from the National Committees on Safety of Medicines. Clinical trials are performed in four phases, ranging from phase I studies performed on healthy volunteers (n = 20-50) to postmarketing (phase IV) studies. The latter are of great importance as they cover large patient populations (n = 2000 to > or = 10,000) and allow detection of rare adverse drug reactions. ADVERSE DRUG REACTIONS: Type B reactions are serious, unpredictable reactions to a drug that necessitate treatment withdrawal. Type A reactions are dose-dependent, and represent the majority of adverse reactions. They are often managed by dose reduction rather than drug withdrawal. ADVERSE REACTIONS TO ANTIHYPERTENSIVE AGENTS: Examples of type B adverse reactions to antihypertensives are the cutaneous and ocular reactions to practolol, and angioneurotic oedema associated with angiotensin converting enzyme inhibitors. Lacidipine, a second-generation calcium antagonist, is an example of a modern antihypertensive agent with a favourable safety profile. The adverse reactions associated with lacidipine are mild to moderate and of the A type, the major ones being those typical of calcium antagonists (headache, flushing and pedal oedema due to vasodilation.
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PMID:Assessing the safety profile of a new antihypertensive agent. 882 81

Following establishment of its efficacy in hypertension and congestive heart failure, the ACE inhibitor lisinopril has now been shown to reduce mortality and cardiovascular morbidity in patients with myocardial infarction when administered as early treatment. The ability of lisinopril to attenuate the detrimental effects of left ventricular remodelling is a key mechanism; however, additional cardioprotective and vasculoprotective actions are postulated to play a role in mediating the early benefit. The GISSI-3 trial in > 19 000 patients has demonstrated that, when given orally within 24 hours of symptom onset and continued for 6 weeks, lisinopril (with or without nitrates) produces measurable survival benefits within 1 to 2 days of starting treatment. Compared with no lisinopril treatment, reductions of 11% in risk of mortality and 7.7% in a combined end-point (death plus severe left ventricular dysfunction) were evident at 6 weeks. Advantages were apparent in all types of patients. Thus, those at high risk-women, the elderly, patients with diabetes mellitus and those with anterior infarct and/or Killip class > 1 -also benefited. These gains in combined end-point events persisted in the longer term, despite treatment withdrawal after 6 weeks in most patients. At 6 months, the incidence rate for the combined end-point remained lower than with control (a 6.2% reduction). The GISSI-3 results concur with those from recent large investigations (ISIS-4, CCS-1, SMILE) of other ACE inhibitors as early management in myocardial infarction. However, the results of the CONSENSUS II trial (using intravenous enalaprilat then oral enalapril) were unfavourable in some patients. These findings, together with the development of persistent hypotension and, to a lesser extent, renal dysfunction among patients in the GISSI-3 trial, have prompted considerable debate over optimum treatment strategies. Present opinion generally holds that therapy with lisinopril or other ACE inhibitors shown to be beneficial may be started within 24 hours in haemodynamically stable patients with no other contraindications; current labelling in the US and other countries reflects this position. There is virtually unanimous agreement that such therapy is indicated in high-risk patients, particularly those with left ventricular dysfunction. The choice of ACE inhibitor appears less important than the decision to treat; it seems likely that these benefits are a class effect. Lisinopril has a tolerability profile resembling that of other ACE inhibitors, can be given once daily and may be less costly than other members of its class. However, present cost analyses are flawed and this latter points remains to be proven in formal cost-effectiveness analyses. In conclusion, early treatment with lisinopril (within 24 hours of symptom onset) for 6 weeks improves survival and reduces cardiovascular morbidity in patients with myocardial infarction, and confers ongoing benefit after drug withdrawal. While patients with symptoms of left ventricular dysfunction are prime candidates for treatment, all those who are haemodynamically stable with no other contraindications are also eligible to receive therapy. Lisinopril and other ACE inhibitors shown to be beneficial should therefore be considered an integral part of the early management of myocardial infarction in suitable patients.
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PMID:Lisinopril. A review of its pharmacology and clinical efficacy in the early management of acute myocardial infarction. 889 68

NEUROHUMORAL SYSTEMS AS SUPERCONTROLLERS: The brain and closely linked hormone systems play a crucial part in short- and long-term cardiovascular control and have many features of adaptive control systems. The cardiovascular control system is a multivariate system, while changes in environmental conditions often result in alterations in system parameters and other non-linearities, in contrast to the fixed parameters of linear control systems. In blood pressure control these features are exemplified by diurnal circadian fluctuations, alterations in lifestyle and psychosocial stress. Because the neurohumoral controllers are involved in virtually all aspects of homeostasis, they can be regarded as supercontrollers. THE CIRCULATORY SYSTEM AND THE BRAIN: Analysis in conscious animals of the effects of circulatory disturbances suggests that the central nervous system integrates information from multiple sources of afferents. Integration of the information associated with most reflex and behavioural disturbances is mediated by many neuron groups at different levels of the neuraxis, including suprapontine brain regions. The disturbances considered include baroreflexes in intact animals, some central actions of alpha-methyldopa and reflex responses to hypoxia and haemorrhage. The operations involve the brain in comparisons of the relative magnitude of different inputs, while the occurrences of non-linear changes in baroreflex properties signify alterations in the parameters of the controller. NEUROHUMORAL MECHANISMS AND CARDIOVASCULAR DEVELOPMENT: Neurohumoral mechanisms also play a key role in cardiovascular development. Increased sympathetic activity early in life causes hypertension in spontaneously hypertensive rats (SHR) and accounts for the differences in blood pressure and structural variables from corresponding values in Wistar-Kyoto (WKY) rats. In contrast, the renin-angiotensin system affects early cardiovascular development in the same way in each strain, so that it is unlikely to be a cause of hypertension in SHR. However, after drug withdrawal following treatment of young rats with the angiotensin converting enzyme inhibitor enalapril, there were between-strain differences in late cardiovascular development. Late development is relatively small in SHR compared to WKY rats, which contributes to the long-term attenuation of hypertension in SHR and to the normalization of blood pressure in WKY rats.
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PMID:Circulatory control and the supercontrollers. 890 3


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