Gene/Protein Disease Symptom Drug Enzyme Compound
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The angiotensin converting enzyme (ACE) inhibitors are a group of effective drugs with a unique mechanism of action. These drugs have proven to be useful for hypertension and congestive heart failure. Early clinical trials of captopril used doses that are now known to be inappropriately high, and dose-related adverse effects were observed frequently. The recognition that lower doses are effective has reduced the incidence of adverse reactions and resulted in improved patient tolerance. When patients are properly selected and correctable risk factors are removed, serious side effects are uncommon. Unfortunately, the early reputation of nephrotoxicity persists, as does the belief that significant blood dyscrasias, endocrine effects and rash are serious risks for the average patient. After wide use of captopril, enalapril and lisinopril, and investigational trials of nearly a dozen newer agents, a sufficiency of clinical observation, experimental evidence and accurate postmarketing recording of events is accumulating to allow insight into the major toxicities with regard to more intelligent patient selection, more rational dosing and proper identification of risk factors. The most common adverse reactions are cough and skin rash. It appears that the agents are generally not cross-reactive with regard to skin rash, although it is not clear whether this effect is drug-specific or class-specific with regard to cough. Statistically but not clinically significant lowering of haemoglobin and hematocrit is common; these effects are inconsequential in most patients. Neutropenia, once thought to be prevalent, now appears to be so only in patients with autoimmune or collagen-vascular disease; the majority of patients outside these groups are at low risk. Hyperkalaemia is a frequent occurrence. This should not be surprising in view of the effect of the ACE inhibitors on plasma aldosterone. When dietary potassium intake is regulated and sources of altered potassium excretion are identified, hyperkalaemia is seldom a serious problem. Identification of sodium and water deficits allows correction before the drugs are started, and the frequency of hypotension and hyperkalaemia caused by the drugs is quite low if these factors are properly managed. An unexpected finding emerging in recent years is the dry cough associated with ACE inhibitor therapy. Its mechanism is not definitely known. Nonsteroidal anti-inflammatory drugs may control this symptom in some patients. The frequent observation of proteinuria in patients taking ACE inhibitors has gained notice and sometimes caused undue alarm. It is difficult to separate disease effects in diabetes and hypertension from true drug effects.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update. 153 95

The pharmacological activity and safety of the new angiotensin converting enzyme (ACE) inhibitor trandolapril (RU 44570) has been evaluated in ten healthy male volunteers given 2 mg once daily for seven days. Assessment criteria included evaluation of plasma ACE and renin activity and aldosterone levels in the supine and standing positions, monitoring of blood pressure, heart rate and electrocardiogram, routine blood and urine laboratory tests, and evaluation of adverse effects. Plasma ACE activity (both in the supine and standing positions) was significantly lower after the first dose and was almost completely suppressed after 7 days of treatment. Plasma renin activity with the subjects in both positions was significantly increased at the end of treatment. Plasma aldosterone did not vary significantly, except for an increase in the standing position after 7 days of wash-out. No significant changes occurred in blood pressure, heart rate, electrocardiogram, blood or urine laboratory tests. No adverse effects were reported, in particular, no orthostatic hypotension, cough or episodes of bronchospasm occurred. It is concluded that oral trandolapril 2 mg o.d. is an effective and long-lasting ACE inhibitor with a good safety profile on repeated dosing. Further studies are warranted to investigate its therapeutic application as well as its safety profile after long-term administration.
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PMID:Pharmacological activity and safety of trandolapril (RU 44570) in healthy volunteers. 164 89

Eleven patients (five women and six men), aged 24-60 years, were treated with the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, with a once-daily dose as the only antihypertensive treatment. Renal artery stenosis was unilateral in eight patients and bilateral in the remaining three. Fibromuscular dysplasia was present in seven patients, and renal arteriosclerotic narrowing was present in the remaining four. All completed a 6-month treatment and went on to a long-term treatment program for a final 24 months, now completed by five patients. Mean pretreatment blood pressure, 187 +/- 19/112 +/- 5 mm Hg (systolic/diastolic; mean +/- SD), was reduced to 148/87 following the drug titration period (1 week), and the same antihypertensive control was maintained throughout the study. Plasma concentration of angiotensin II, aldosterone, and serum ACE activity were effectively reduced for at least 24 h following drug administration. Serum concentrations of lisinopril varied individually and rose in two patients with moderate renal failure. Renal function was well maintained, and control renography revealed no worsening of renal artery stenosis or renal function. The drug was well tolerated without side effects other than cough in one patient. We conclude that lisinopril monotherapy is highly effective in renovascular hypertension. Drug safety was demonstrated by the lack of serious side effects.
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PMID:Long-term monotherapy with lisinopril in renovascular hypertension. 244 55

The renin-angiotensin system has a wide range of physiological actions, and thus interference with the system has attractive therapeutic potential. The orally active angiotensin converting enzyme (ACE) inhibitors have so far been the most successful drugs in this area. They lower arterial pressure both in renovascular and essential hypertension, and their effects are enhanced by concomitant diuretic therapy or dietary salt restriction. Since, in renovascular hypertension, the affected kidney depends on enhanced local generation of angiotensin II to help preserve its function, the circulation and excretory capacity of this kidney may be compromised with ACE inhibition. ACE inhibitors can improve exercise tolerance and diminish cardiac ventricular arrhythmias in patients with heart failure. Because these drugs lower plasma aldosterone, they tend to correct potassium deficiency and hypokalemia, which may have been induced by diuretic treatment. Hypotension can occur with the first dose of ACE inhibitor, especially in sodium-depleted subjects; in patients on prior antihypertensive therapy, particularly if this includes a diuretic; and in the elderly. Not all of the actions of ACE inhibitors are necessarily due to lowering of plasma angiotensin II: accumulation of kinins may be responsible for some of the effects and side effects. Common to all ACE inhibitors are occasional rashes, cough, and, more rarely, angioedema. Apparently peculiar to captopril, and less often seen with the lower doses now employed, are taste disturbance, proteinuria, and marrow depression. ACE inhibitors, should not be used in pregnant women.
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PMID:Converting enzyme inhibitors in the treatment of hypertension. 248 62

Synthetic orally active angiotensin-converting enzyme (ACE) inhibitors have been successfully used in the treatment of congestive heart failure and hypertension, particularly in hypertensive subjects with increased renin-angiotensin-aldosterone-system activity. Adverse skin reactions, angioneurotic oedema and rapidly decreasing lung function in asthmatics have been reported following medication with ACE inhibitors. Furthermore, these drugs have been associated with a persistent dry cough in subjects without previous known bronchial hyper-reactivity. There is reason to believe that an ACE inhibitor-induced cough is due to an increased inflammatory state in the airways of susceptible individuals, and that this cough might thereby have pathophysiological features in common with the cough seen as an early symptom of asthma. All inflammatory responses, wheal and flare reactions, infiltration of neutrophils, eosinophils, basophils and monocytes were enhanced by ACE inhibitors. A dose-response relationship for the proinflammatory effect of the ACE inhibitor has been demonstrated.
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PMID:Angiotensin-converting enzyme inhibitors and their influence on inflammation, bronchial reactivity and cough. A research review. 268 32

Adverse effects of converting enzyme inhibitors are either substance-specific (neutropenia, proteinuria, skin rashes, taste disturbances) or due to the converting enzyme inhibition (hypotension, functional renal insufficiency, hyperkalemia, cough, angioedema). They are rare nowadays because of better knowledge of the pharmacokinetics and -dynamics of the converting enzyme inhibitors, resulting in lower dosage, and because of identifying patients at high risk. The dosage must be adjusted according to renal function, in order to prevent accumulation and toxicity. In addition to patients with renal insufficiency, patients at high risk are those with a stimulated renin-angiotensin-aldosterone system, i.e. patients with renovascular hypertension or heart failure. Patients with collagen vascular disease, for example, systemic lupus erythematosus or scleroderma, should not be considered for long-term therapy with converting enzyme inhibitors because of the increased risk of neutropenia. Life-threatening angioedema may develop, mainly during the first few hours after drug administration.
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PMID:[Angiotensin-converting enzyme inhibition: side effects and risks]. 285 Jun 87

The effects of cilazapril on exercise tolerance and neurohumoral factors were investigated in old myocardial infarction (OMI) patients with asymptomatic heart failure and reduced left ventricular ejection fraction. Cilazapril (0.5 mg) was administered once daily to OMI patients (n = 20) [NYHA class I, sinus rhythm, ejection fraction by radionuclide scanning < 50% (36.8 +/- 9.1%, mean +/- SD)]. Two weeks later, five patients were excluded from the study because of cough or hypotension, and 15 patients received 1.0 mg cilazapril once daily for the next 6 weeks. Exercise tolerance, neurohumoral factors and ejection fraction were measured in OMI patients before and after administration of cilazapril. Seven age-matched healthy adults served as the controls. OMI patients had latent heart failure because their exercise tolerance values and aldosterone levels were lower and alpha-atrial natriuretic polypeptide levels were higher than those in healthy subjects. In OMI patients, 8 weeks after cilazapril administration, exercise duration increased from 545 +/- 59 to 590 +/- 74 sec (p < 0.05), anaerobic threshold from 17.5 +/- 3.2 to 20.1 +/- 2.8 ml/min/kg (p < 0.05), peak-VO2 from 23.5 +/- 4.7 to 27.1 +/- 4.4 ml/min/kg (p < 0.05), plasma renin activity from 1.34 +/- 1.13 to 5.82 +/- 5.47 ng/ml/hr (p < 0.01) and alpha-atrial natriuretic polypeptide decreased from 100.7 +/- 44.3 to 80.5 +/- 28.0 pg/ml (p < 0.05). In patients with asymptomatic left ventricular dysfunction after myocardial infarction, 8 week's cilazapril administration improved exercise tolerance and neurohumoral conditions.
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PMID:[Effect of cilazapril on exercise tolerance and neurohumoral factors in patients with asymptomatic chronic heart failure after myocardial infarction]. 852 61

The past few decades have seen a remarkable development in the field of pharmacological therapy, one of the most notable examples being the treatment of arterial hypertension. Some of the early anti-hypertensive agents were relatively crude by today's standards, but gradually efficacy, tolerability, or both, of blood pressure-lowering (BP) drugs have been improved. It is presently possible to choose from a number of effective and well-tolerated compounds for the treatment of hypertension. The latest additions to the anti-hypertensive armamentarium are the angiotensin II receptor antagonists, the most advanced of these being losartan. It is perhaps most relevant to compare losartan to the angiotensin converting enzyme (ACE) inhibitors, another class of anti-hypertensive agents which acts mainly by interfering with the renin-angiotensin-aldosterone system (RAAS). Studies have shown that losartan lowers BP at least as effectively as ACE inhibitors. However, the side-effect profile of losartan is more favourable. In particular cough, a relatively common side-effect of ACE inhibitors, has been shown to be significantly less common during losartan treatment. This is probably because losartan does not interfere with bradykinin metabolism, unlike the ACE inhibitors. Regarding the reversal of left ventricular hypertrophy (LVH), a powerful risk indicator for cardiovascular disease, we have shown that losartan is more effective in this regard than treatment with the beta-blocker atenolol. It appears, based on these and other findings, that interference with the RAAS is particularly useful in causing reversal of the cardiovascular hypertrophic changes. The prognostic implications remain to be demonstrated, but it would be logical to expect a benefit from this effect. It was recently shown that polymorphism of the ACE gene is associated with increased risk of coronary heart disease even in the absence of conventional risk factors. If these findings are confirmed the interest in interfering with the RAAS as a therapeutic modality in hypertension would obviously be strengthened. It is not easy to predict the future role of any new therapeutic modality. The positive relation between efficacy and tolerability of losartan, as well as the fact that several observations suggest that interference with the RAAS could be favourable from a prognostic point of view, suggest that losartan may come to play an important role in the future treatment of hypertension.
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PMID:The future role of losartan. 858 83

Pharmacologic agents that attenuate the influence of the renin-angiotensin-aldosterone system are known to reduce systemic arterial blood pressure through vasodilatory action and enhanced renal clearance of sodium and water. Angiotensin-converting enzyme inhibitors are known to antagonize the renin-angiotensin-aldosterone system through their ability to inhibit conversion of angiotensin I to angiotensin II. A new class of antihypertensive agents, angiotensin-II receptor antagonists, has recently been developed. These agents specifically block the receptor for angiotensin II, thereby limiting angiotensin II-mediated vasoconstriction and reducing aldosterone secretion. These effects result in a reduction in systemic arterial blood pressure through reduced vascular tone and enhanced sodium and water clearance. Clinical trials have demonstrated the efficacy of these agents in reducing blood pressure. These new antihypertensive agents also have uricosuric actions and are well tolerated, with a low incidence of cough and angioedema, side effects that are seen with angiotensin-converting enzyme inhibitors. Clinical trials are underway to see if these drugs will be useful in the treatment of diseases other than hypertension, such as congestive heart failure and chronic renal disease.
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PMID:Angiotensin-II receptor antagonists: a new class of antihypertensive agents. 862 40

The renin-angiotensin-aldosterone system (RAAS) plays an important role in both the short-term and long-term regulation of arterial blood pressure, and fluid and electrolyte balance. The RAAS is a dual hormone system, serving as both a circulating and a local tissue hormone system (i.e., local mediator) as well as neurotransmitter or neuromediator functions in CNS. Control of blood pressure by the RAAS is exerted through multiple actions of angiotensin II, a small peptide which is a potent vasoconstrictor hormone implicated in the genesis and maintenance of hypertension. Hypertension is a primary risk factor associated with cardiovascular, cerebral and renal vascular disease. One of the approaches to the treatment of hypertension, which may be considered as a major scientific advancement, involves the use of drugs affecting the RAAS. Pharmacological interruption of the RAAS was initially employed in the late 1970s with the advent of the angiotensin converting enzyme (ACE) inhibitor, captopril. ACE inhibitors have since gained widespread use in the treatment of mild to moderate hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy. As the roles of the RAAS in the pathophysiology of several diseases was explored, so did the realization of the importance of inhibiting the actions of angiotensin II. Although ACE inhibitors are well tolerated, they are also involved in the activation of bradykinin, enkephalins, and other biologically active peptides. These actions result in adverse effects such as cough, increased bronchial reactivity, and angioedema. Thus, the goal of achieving a more specific blockade of the effects of angiotensin II than is possible with ACE inhibition. The introduction of the nonpeptide angiotensin II receptor antagonist losartan in 1995 marked the achievement of this objective and has opened new vistas in understanding and controlling the additional biological effects of angiotensin II. Complementary investigations into the cloning and sequencing of angiotensin II receptors have demonstrated the existence of a family of angiotensin II receptor subtypes. Two major types of angiotensin II receptors have been identified in humans. The type 1 receptor (AT1) mediates most known effects of angiotensin II. The type 2 receptor (AT2), for which no precise function was known in the past, has gained importance recently and new mechanisms of intracellular signalling have been proposed. This review presents recent advances in angiotensin II receptor pharmacology, molecular biology, and signal transduction, with particular reference to the AT1 receptor. Excellent reviews have appeared recently on this subject.
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PMID:Angiotensin II receptors-antagonists, molecular biology, and signal transduction. 1009 99


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