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)

Impaired left ventricular diastolic function is an indicator of early stages of heart disease. In cardiac failure it is not necessarily associated with impaired systolic function and correlates more closely with clinical symptoms or load tolerance. Pharmacotherapy leading to improved diastolic parameters improves also the clinical condition of cardiac failure. Based on data in the literature, the authors analyze drugs which exert a favourable effect on left ventricular diastolic function: ACE inhibitors, calcium channel blockers, beta adrenergic agonists, phosphodiesterase inhibitors, diuretic and direct vasodilating agents, from the aspect of clinical administration.
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PMID:[Pharmacotherapy of diastolic dysfunction in heart failure]. 821 30

Several important questions remain to be answered by future research. First, it is unclear whether any abnormal index of diastolic function can be used to estimate disease severity, or to prognostically identify patients who will subsequently develop systolic abnormalities or frank left ventricular dysfunction. A temporal relationship between the appearance of diastolic dysfunction and ultimate left ventricular decompensation may, theoretically, exist, but such a relationship has yet to be established. Second, a growing body of evidence indicates that pharmacologic therapy with Ca2+ channel antagonists, beta-adrenergic agonists or antagonists, phosphodiesterase inhibitors, or angiotensin converting enzyme inhibitors may acutely or chronically benefit certain patients with diastolic dysfunction. Whether the impact of early recognition and therapeutic intervention in patients with diastolic dysfunction can be translated into an improvement of quality of life or enhanced survival remains unknown. Third, recent evidence indicates that fundamental changes in the biochemistry of the cardiac myocyte may represent a final common pathway for the development of congestive heart failure resulting from intrinsic cardiac disease. Altered expression of genes coding for the ATP-dependent Ca2+ pumps in the sarcolemma and the sarcoplasmic reticulum, regulatory proteins such as phospholamban, and the proteins composing the contractile apparatus have been identified that play critical roles in the pathophysiology of myocardial failure, and have important implications for potential pharmacologic therapy. Future research will more clearly elucidate these cellular and biochemical mechanisms of left ventricular failure. Lastly, although intravenous and inhalational anesthetics produce derangements in normal diastolic function to varying degrees, whether the effects of these agents on diastolic performance are exacerbated in disease processes manifested by abnormal diastolic mechanisms requires further evaluation.
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PMID:Left ventricular diastolic function in the normal and diseased heart. Perspectives for the anesthesiologist (2). 823 87

The clinical syndrome of congestive heart failure remains a therapeutic dilemma and challenge for the physician in 1992. This is a disease process that appears to be increasing in frequency and continues to carry an unacceptably high mortality rate. For years it has been well recognized that the combination of digoxin, Lasix and vasodilator therapy improved symptoms in these patients and decreased hospitalization, but did not increase survival. It was not until 1986 that the combination of digoxin, Lasix, Isordil, and hydralazine was shown to increase survival. Further significant improvement in quality of life and survival has recently been established in three large clinical trials, and it is now safe to say that the standard of care for symptomatic congestive heart failure in 1992 is digoxin, furosemide, and an ACE inhibitor, with the survival trials favoring the ACE inhibitor enalapril. The IV inotropic drug dobutamine remains the mainstay of pharmacological therapy for the treatment of severely refractory heart failure. Unfortunately, the phosphodiesterase inhibitors--amrinone, milrinone, and enoximone--have demonstrated unacceptable clinical side effects and have been withdrawn from further clinical study. In spite of these promising developments, the mortality and morbidity of congestive heart failure remains unacceptably high, and continued investigation in the new fields of pharmacology and the pathophysiology of congestive heart failure still must be aggressively pursued.
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PMID:Inotropic therapy of the failing myocardium. 841 61

Until recently, inotropic therapy has been regarded as the most direct remedy for the left ventricular systolic dysfunction that often underlies the development of heart failure. Nevertheless, all the agents with significant inotropic properties that have been evaluated to date (such as beta adrenergic stimulants, phosphodiesterase inhibitors, and high-dose vesnarinone) showed significant increases in mortality with long-term administration. However, it is noteworthy that the participants in trials to evaluate inotropic therapy were not representative of geriatric heart failure patients for age, gender, and comorbidity. Thus, results from these studies must be interpreted cautiously when treatment for chronic heart failure must be applied to elderly subjects. At present, digitalis is the only inotropic agent recommended for long-term treatment, because it improves symptoms and prevents disease progression through neurohormonal and baroreceptor mechanisms; nevertheless, its long-term safety is still undetermined. The role of low-dose vesnarinone, pimobendan and ibopamine, which share neurohormonal, rather than inotropic, mechanisms of action, is still under investigation. Pending the definition of these issues, ACE-inhibitors and diuretics remain the mainstay of therapy for chromic heart failure.
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PMID:Inotropic agents in older patients with chronic heart failure--current perspectives. 873 6

The regulation of fatty acid oxidation in isolated myocytes was examined by manipulating mitochondrial acetyl-CoA levels produced by carbohydrate and fatty acid oxidation. L-carnitine had no effect on the oxidation of [U-14C]glucose, but stimulated oxidation of [1-14C]palmitate in a concentration-dependent manner. L-carnitine (5 mM) increased palmitate oxidation by 37%. The phosphodiesterase inhibitor, enoximone (250 microM), also increased palmitate oxidation by 51%. Addition of L-carnitine to enoximone resulted in a two-fold increase of palmitate oxidation. Whereas, dichloroacetate (DCA, 1 mM), which stimulates PDH activity, decreased palmitate oxidation by 25%. Furthermore, the addition of DCA to myocytes preincubated with either L-carnitine or enoximone, had no effect on the carnitine-induced stimulation of palmitate, and reduced that of enoximone by 50%. Varied concentrations of DCA decreased the oxidation of palmitate and octanoate; but increased glucose oxidation in myocytes. The rate of efflux of acetylcarnitine was highest when pyruvate was present in the medium compared to efflux rates in presence of palmitate or palmitate plus glucose. Although the addition of L-carnitine plus enoximone resulted in a two-fold increase in palmitate oxidation, acetylcarnitine efflux was minimal under these conditions. Acetylcarnitine efflux was highest when pyruvate was present in the medium. These rates were dramatically decreased when myocytes were preincubated with enoximone, despite the stimulation of palmitate oxidation by this compound. These data suggest that: (1) fatty acid oxidation is influenced by acetyl-CoA produced from pyruvate metabolism; (2) L-carnitine may be specific for mitochondrial acetyl-CoA derived from pyruvate oxidation; and (3) it is probable that acetyl-CoA from beta-oxidation of fatty acids is directly channeled into the citric acid cycle.
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PMID:Regulation of fatty acid oxidation by acetyl-CoA generated from glucose utilization in isolated myocytes. 876 22

By means of CM-Sephadex C-25, DEAE-Sephadex A-50, Sephadex G-200, and Sephadex G-75 chromatographies, a lupus anticoagulant like protein (LALP) from Agkistrodon halys brevicaudus was purified. On SDS-PAGE, the purified LALP had a molecular weight of 25,500 daltons under non-reducing condition and 15,000 daltons under reducing condition. The isoelectric point was pH 5.6. Its N terminal amino acid sequencing revealed a mixture of 2 sequences: DCP(P/S)(D/G)WSSYEGH(C/R)(Q/K). It was devoid of phospholipase A, fibrino(geno)lytic, 5'-nucleotidase, L-amino acid oxidase, phosphomonoesterase, phosphodiesterase and thrombin-like activities, which were found in crude venom. In the presence of LALP, PT, aPTT, and dRVVT of human plasma were markedly prolonged and its effects were concentration-dependent but time-independent. The inhibitory effect of LALP on the plasma clotting time was enhanced by decreasing phospholipid concentration in TTI test. The individual clotting factor activity was not affected by LALP when higher dilutions of LALP-plasma mixture were used for assay. Russell's viper venom time was shortened when high phospholipid confirmatory reagent was used. Therefore, the protein has lupus anticoagulant property.
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PMID:Purification and characterization of lupus anticoagulant like protein from Agkistrodon halys brevicaudus venom. 897 23

Understanding the mechanism of action and the pharmacokinetic properties of vasodilatory drugs facilitates optimal use in clinical practice. It should be kept in mind that a drug belongs to a class but is a distinct entity, sometimes derived from a prototype to achieve a specific effect. The most common pharmacokinetic drug improvement is the development of a drug with a half-life sufficiently long to allow an adequate once-daily dosage. Developing a controlled release preparation can increase the apparent half-life of a drug. Altering the molecular structure may also increase the half-life of a prototype drug. Another desirable improvement is increasing the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site. This is especially important for vasodilatory drugs which may be administered over decades for the treatment of hypertension, which usually does not interfere with subjective well-being. Compliance is greatly increased with once-daily dosing. Vasodilatory agents cause relaxation by either a decrease in cytoplasmic calcium, an increase in nitric oxide (NO) or by inhibiting myosin light chain kinase. They are divided into 9 classes: calcium antagonists, potassium channel openers, ACE inhibitors, angiotensin-II receptor antagonists, alpha-adrenergic and imidazole receptor antagonists, beta 1-adrenergic agonist, phosphodiesterase inhibitors, eicosanoids and NO donors. Despite chemical differences, the pharmacokinetic properties of calcium antagonists are similar. Absorption from the gastrointestinal tract is high, with all substances undergoing considerable first-pass metabolism by the liver, resulting in low bioavailability and pronounced individual variation in pharmacokinetics. Renal impairment has little effect on pharmacokinetics since renal elimination of these agents is minimal. Except for the newer drugs of the dihydropyridine type, amlodipine, felodipine, isradipine, nilvadipine, nisoldipine and nitrendipine, the half-life of calcium antagonists is short. Maintaining an effective drug concentration for the remainder of these agents requires multiple daily dosing, in some cases even with controlled release formulations. However, a coat-core preparation of nifedipine has been developed to allow once-daily administration. Adverse effects are directly correlated to the potency of the individual calcium antagonists. Treatment with the potassium channel opener minoxidil is reserved for patients with moderately severe to severe hypertension which is refractory to other treatment. Diazoxide and hydralazine are chiefly used to treat severe hypertensive emergencies, primary pulmonary and malignant hypertension and in severe preeclampsia. ACE inhibitors prevent conversion of angiotensin-I to angiotensin-II and are most effective when renin production is increased. Since ACE is identical to kininase-II, which inactivates the potent endogenous vasodilator bradykinin, ACE inhibition causes a reduction in bradykinin degradation. ACE inhibitors exert cardioprotective and cardioreparative effects by preventing and reversing cardiac fibrosis and ventricular hypertrophy in animal models. The predominant elimination pathway of most ACE inhibitors is via renal excretion. Therefore, renal impairment is associated with reduced elimination and a dosage reduction of 25 to 50% is recommended in patients with moderate to severe renal impairment. Separating angiotensin-II inhibition from bradykinin potentiation has been the goal in developing angiotensin-II receptor antagonists. The incidence of adverse effects of such an agent, losartan, is comparable to that encountered with placebo treatment, and the troublesome cough associated with ACE inhibitors is absent.
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PMID:Clinical pharmacokinetics of vasodilators. Part I. 964 8

We experienced a Duchenne muscular dystrophy (DMD) patient with severe congestive heart failure (CHF) successfully treated with milrinone. He had been diagnosed as having CHF since 24 years of age when he began to have mechanical ventilation with a nasal mask at home. Although angiotensin converting enzyme (ACE) inhibitor was effective for his CHF, cardiac function worsened year by year. Respiratory infection triggered the exacerbation of CHF at the end of 1997 (27 years old). On admission to our hospital on January 7, 1998, PaO2 was 48 mmHg and cardiothoracic ratio (CTR) was 62%. Both ventricles were dilated and ventricular wall motility was markedly reduced on ultrasonocardiography. Ejection fraction of the left ventricle (LVEF) was 5%. Serum brain natriuretic peptide (BNP) was 760 pg/ml. Continuous intravenous infusion of milrinone was started on January 8 at the rate of 0.25-0.35 microgram/kg/min. His general condition improved and LVEF increased up to 15% on January 27. No serious side effects were observed. Even after milrinone withdrawal, his cardiac condition remained stable until the end of February 1998. Temporary deteriorated CHF due to urinary tract infection was successfully treated by chemotherapy and milrinone. Subsequently he was discharged on March 13 and could stay in his home for 7 weeks uneventfully with milrinone infusion therapy. When he was readmitted to the hospital for evaluation of CHF on April 30, CTR was 44%, LVEF was 20% and BNP was 44 pg/ml. CHF is one of the life threatening complications for DMD. Although catecholamine is a well utilized agent for advanced CHF, it has limited effect in DMD, because beta receptors are down-regulated due to long-lasting cardiac dysfunction. Increased heart rate and arrhytmia are also serious problems during catecholamine therapy. Milrinone is a type III phosphodiesterase inhibitor having inotropic and vasodilatic actions with modest increase of heart rate and little torelance. Milrinone is probably effective in improving CHF of DMD and has less side effects as compared to catecholamine. We concluded that milrinone might improve quality of lives of DMD patients with advanced CHF, although further cumultative studies are necessary to confirm its effectiveness and safety.
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PMID:[Effective milrinone therapy to a Duchenne muscular dystrophy patient with advanced congestive heart failure]. 1050 90

Heart failure is common in patients aged over 65 years, and is the fourth leading cause of hospitalization in the United States. Treatment of congestive heart failure involves remodeling the cardiac chamber with ventricular dilatation. New approaches to resolve this problem include medical therapies (digoxin, diuretics, ACE inhibitors, beta-blockers and phosphodiesterase inhibitors) to stabilize patients, followed by chamber remodeling. As yet, surgical intervention in advanced heart failure has been contraindicated, but newly evolving strategies show significant promise. It appears possible that patients can receive surgical therapy to improve cardiac function, followed by state-of-the-art medical therapy for congestive heart failure. This combined medical/surgical approach has led to the evolution of a new subspecialty within cardiology that deals with the management of heart failure.
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PMID:New surgical options for the failing heart. 1051 85

Newer drug therapy for patients with cardiomyopathies has been introduced with standard one. Beta-blocker therapy improves the prognosis in patients with ischemic and non-ischemic DCM and even in asymptomatic ones with LV dysfunction. The combined therapy of ACE inhibitor and angiotensin II receptor blocker, the intermittent intravenous infusion of inotropic agents and the supplement of phosphodiesterase inhibitor on induction of beta-blocker therapy also elucidate the effectiveness in DCM patients.
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PMID:[Medical treatment for cardiomyopathies]. 1088 89


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