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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In congestive heart failure (CHF), even today, pharmacotherapy renders primarily only symptomatic improvement. The success of the treatment is basically dependent on the degree of functional myocardial impairment, that is, the condition of the inadequately treatable underlying disease. Treatment should be differentially oriented to the nature of the LV dysfunction as systolic or diastolic whereby the latter may account for 20 to 40% of those with CHF. In the case of diastolic LV dysfunction, because of the impaired compliance, vasodilators are not beneficial since small changes in volume may cause marked changes in filling pressures and vice versa. Additionally, inotropic substances are unfavorable since they further increase filling pressure and impedance, that is, diastolic LV function may become more compromised. For systolic LV dysfunction both vasodilators and positive inotropic substances can be employed. Some unsettled issues remaining include the appropriate time to begin treatment, the most suitable form of combined treatment and the best dosing regimens. Digitalis, as dobutamine, increases measured contractility; those seen to profit from digitalis include symptomatic patients with LV dilatation and impaired pump function as well as patients with supraventricular tachyarrhythmias. Prior to use of positive inotropic drugs in CHF, consideration should be given to whether favorable acute effects can be maintained during longterm treatment, adverse reactions such as arrhythmogenicity are acceptable, and the actions on myocardial oxygen balance. New nonglycoside positive inotropic agents which can also be administered orally, acutely improve hemodynamics; these include catecholamine derivatives, phosphodiesterase inhibitors (PDH). Both substance groups increase contractility but arrhythmogenicity as well, in general via increased concentrations of intracellular cyclic AMP. Reservations regarding the use of positive inotropic drugs for CHF have been supported by the results of studies showing that beta 1 agonists such as prenalterol and beta 2 agonists such as salbutamol or pirbuterol, due to down-regulation of beta-receptor density, are not capable of maintaining improved contractility during chronic treatment; intermittent dobutamine treatment resulted in higher mortality; beta-blockers without intrinsic sympathomimetic activity reduced mortality in patients with CHF after myocardial infarction while on use of beta-receptor blockers with intrinsic sympathomimetic activity, this favorable effect was not observed; during chronic PDH treatment, there was an unfavorable one-year mortality rate (50 to 100%); a controlled study with amrinone did not show a higher mortality than placebo. For most PDH, it is not known with certainty at which therapeutically effective dose the positive inotropic effect can best be realized and whether the acute hemodynamic effects are not predominantly attributable to the vasodilatory properties.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:[Chronic heart failure: effect and evaluation of therapy with positive inotropic substances]. 219 20

The pharmacologic treatment of heart failure and low cardiac output syndrome in the cardiac surgical patient continues to be a challenge in the nursing management of these patients. While the catecholamines have been of proven inotropic benefit over the years, their inherit risks of increased myocardial oxygen consumption, tachyphylaxis and poor tolerance in many patients have lead to the search for other medications to augment cardiac performance. Amrinone, the only drug available for use in the U.S. from the class of phosphodiesterase inhibitors, acts as both an inotrope and vasodilator to increase cardiac output without an increase in myocardial oxygen consumption. This paper reviews pharmacological management of heart failure in the cardiac surgical patient and nursing considerations specific to amrinone and combination inotropic therapy management.
...
PMID:Management of heart failure in cardiac surgical patients: amrinone and other pharmacologic agents. 226 43

Before it reaches the decompensation stage, heart failure is characterized by symptoms which occur only during exercise. It is therefore rational to believe that the effectiveness of treatments of heart failure should be evaluated by the improvement they produce in tolerance to stress. This tolerance can be evaluated by exercise tests which may take different forms. The most common is a progressive load test on bicycle ergometer or treadmill. Among the indices used to assess tolerance to stress, the total duration of the exercise test until symptoms develop is a variable subject to fluctuations which may be independent of the patient's cardiovascular state. Measurement of oxygen consumption at peak exercise level is usually preferred, being unrelated to the nature of the stress and much more reproducible and sensitive to changes. Among the pharmacological treatments of heart failure, only chronic vasodilator therapy, notably with angiotensin-converting enzyme inhibitors, has proved constantly effective on the various ergometric indices. In the literature, the effects of digitalis compounds, dihydralazine and alpha-blockers are inconstant. Among the new treatments of heart failure, phosphodiesterase inhibitors may improve tolerance to stress, as does Corwin which may prolong the total duration of exercise. Its effect on oxygen consumption has not yet been evaluated. Performance at exercise is almost never improved by acute treatment with any pharmacological agent, and the same remarks applies to short-term heart transplantation. The reason for this is that heart failure is associated with a physical deconditioning syndrome due to abnormalities of the arterial dilatation capacity in skeletal muscles, and with muscular metabolic abnormalities due to a defective oxygen utilization by these muscles.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:[Usefulness of exercise tests in the evaluation of the effects of treatment in chronic cardiac insufficiency]. 226 63

Nine consecutive patients having severe idiopathic dilated cardiomyopathy were studied for their response in ventricular function, coronary sinus blood flow and myocardial oxygen consumption, lactate extraction and efficiency following incremental doses of dobutamine, followed by the combination of dobutamine and the phosphodiesterase inhibitor amrinone. Results, presented as baseline and the response to the peak dose (15 micrograms/kg/min) of dobutamine and to the combination of dobutamine and amrinone (each at 15 micrograms/kg/min) (differences compared with baseline) were: wedge pressure decreased from 28 +/- 7 to 26 +/- 8 mm Hg (p = NS) and to 20 +/- 6 mm Hg (p less than 0.01); cardiac index rose from 1.47 +/- 0.44 L/min/m2 to 2.89 +/- 1.1 L/min/m2 (p less than 0.01) and to 3.64 +/- 1.05 L/min/m2 (p less than 0.001); myocardial oxygen consumption remained invariant (18 +/- 8, 17 +/- 5, and 19 +/- 5 ml/min) despite progressive increments in minute work from 2.96 +/- 1.1 to 6.98 +/- 3.9 kg - m/min (p less than 0.01) and to 9.38 +/- 4.3 kg - m/min (p less than 0.001); myocardial lactate extraction rose from 21 +/- 10% to 30 +/- 15% (p = NS) and to 35 +/- 10% with the addition of amrinone (p less than 0.01). No patient had net lactate efflux into the coronary sinus, and myocardial efficiency improved from 9.5 +/- 5% to 21.7 +/- 13.0% (p less than 0.01) and to 28.0 +/- 18.0% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Myocardial energetics and efficiency in patients with idiopathic cardiomyopathy: response to dobutamine and amrinone. 232 8

Amrinone, a new nonadrenergic, nonglycosidic agent with combined positive inotropic and vasodilating properties, was approved recently for parenteral use in the treatment of left ventricular failure. Its mechanism of action is mediated primarily by selective phosphodiesterase fraction III inhibition, although at high doses alterations of calcium transport may occur. Acute hemodynamic changes produced by amrinone include augmentation of cardiac output and decreases in pulmonary capillary wedge pressure, right atrial pressure and systemic vascular resistance. Heart rate and blood pressure remain unaltered. Myocardial oxygen consumption declines concomitantly with the decrease in systolic wall tension. The efficacy of amrinone is comparable to that of dobutamine and dopamine. Synergistic interactions with catecholamines and vasodilators are described. Adverse effects are minimal, with dosage limited predominantly by decreases in filling pressures.
...
PMID:Intravenous use of amrinone for the treatment of the failing heart. 241 Nov 22

Methylxanthines are primary agents used in treatment of hypersensitivity disease. Because polymorphonuclear leukocyte (PMN) activation is associated with generation of potent inflammatory mediators, xanthine effects on the PMN respiratory burst were studied. Enprofylline, a xanthine with important therapeutic potential, does not antagonize adenosine and was contrasted with theophylline. Although enprofylline was more potent at low concentrations, both drugs exhibited dose-dependent inhibition of PMN activation at concentrations greater than 10 mumol/L (1.8 micrograms/ml). Oxygen metabolite generation was decreased by 30% to 40% at therapeutic drug concentrations and by 85% at 1 mmol/L of theophylline. Inhibition by isoproterenol or prostaglandin E2 but not dibutyryl cAMP was potentiated by either xanthine. Isoproterenol effects were also increased when isoproterenol was evaluated in whole blood specimens obtained from subjects after a loading dose of aminophylline. Although these results were most compatible with cAMP phosphodiesterase inhibition, other commonly proposed mechanisms of methylxanthine activity were also studied. Theophylline but not enprofylline blocked adenosine inhibition of PMN activation. Neither xanthine shifted the calcium dose-response when PMNs were activated with calcium ionophore. Because oxygen metabolites generated by the FMN are mediators of inflammation and hypersensitivity, direct inhibition of PMN activation as well as potentiation of catecholamine activity may be important therapeutic effects of theophylline and enprofylline.
...
PMID:Therapeutic concentrations of theophylline and enprofylline potentiate catecholamine effects and inhibit leukocyte activation. 243 4

The present experiments were performed in anesthetized dogs in order to determine if DN-9693, a new antiplatelet agent known to selectively inhibit cyclic AMP phosphodiesterase (PDE), and isobutylmethylxanthine (IBMX), which inhibits both cyclic AMP and GMP PDEs, have different cardiovascular actions. With intra-arterial administration into the left anterior descending coronary, femoral, cranial mesenteric and renal arterial beds perfused at constant pressure with autologous blood, both agents increased blood flow in a similar dose range. DN-9693 was longer-acting than IBMX. Both agents were nearly equi-effective in the femoral circulation, but DN-9693 was 1.5-2 times less effective than IBMX in the others. With intravenous administration, both agents were equi-effective in increasing the maximum rate of rise of left ventricular pressure heart rate and myocardial oxygen consumption and in reducing mean blood pressure. However, DN-9693 was less effective in increasing coronary sinus outflow than IBMX. These results suggest the following: 1) Vasodilation in the somatic rather than the visceral circulation is important in reducing mean blood pressure. 2) Cyclic GMP may not be involved in the cardiac action of PDE-inhibitors. 3) Cyclic GMP may be involved in the vasodilator effect of PDE-inhibitors in the coronary, mesenteric and renal circulations but least involved in the femoral circulation.
...
PMID:Comparison of vasodilator effects of DN-9693, a selective inhibitor of cyclic AMP phosphodiesterase, and isobutylmethylxanthine, a non-selective one, in dogs. 244 35

The role of structural features of sulmazole, an imidazo(4,5-b)pyridine, in its inotropic action was examined by comparison with its reduced (4-methylthiophenyl) analog EMD 46512 and the corresponding imidazo(4,5-c)pyridine isomers isomazole and EMD 41000 on isolated guinea-pig papillary muscles and right atria and on Na,K-ATPase and phosphodiesterase III isolated from guinea-pig hearts. The pyridine nitrogen position in sulmazole was crucial for affinity to Na,K-ATPase (IC50 = 350 microM) because the imidazo(4,5-c)pyridines had little effect. Participation of Na,K-ATPase inhibition in sulmazole's inotropic effect (EC50 = 180 microM) was suggested by synergism with the Na channel activator germitrine. The methylsulfinyl oxygen at the phenyl ring decreased the affinity to Na,K-ATPase of sulmazole 40-fold: The reduced analog EMD 46512 was a potent inhibitor of Na,K-ATPase (IC50 = 8.5 microM) and a more potent inotropic agent (EC50 = 8.2 microM) that appeared to act predominantly through Na,K-ATPase inhibition. Micromolar through Na,K-ATPase inhibition. Micromolar IC50s for inhibition of phosphodiesterase III were 49 (sulmazole), 34 (EMD 46512), 18 (isomazole), and 13 (EMD 41000). Participation of this mechanism in the inotropic effect of sulmazole, isomazole, and EMD 41000, but not EMD 46512, was indicated by augmentation of slow action potentials, synergism with histamine, inhibition by carbachol, and (with the exception of EMD 41000) a positive chronotropic effect on the right atrium. Sulmazole appeared to combine the actions of its 4-methylthiophenyl analog EMD 46512 (an inhibitor of Na,K-ATPase) and of its imidazo(4,5-c)pyridine isomer isomazole (an inhibitor of phosphodiesterase III).
...
PMID:Imidazopyridines: roles of pyridine nitrogen position and methylsulfinyl oxygen for in vitro positive inotropic mechanism and chronotropic activity. 247 14

Cardiac failure is treated with increasing success by phosphodiesterase-III (PDE-III) inhibitors such as amrinone, milrinone, and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and beta-receptors. They have positive inotropic, positive lusitropic, and vasodilatatory properties; myocardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III, leading to an increased cAMP concentration in myocardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole, amrinone, and enoximone resulted in preload and afterload reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance; they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmax, while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myocardial oxygen consumption showed no clinically relevant alterations. In patients with angiographically documented coronary artery disease, the anti-ischemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myocardial efficacy, indicating its positive inotropic and lusitropic properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDE inhibitors. The anti-ischemic properties of these drugs need further evaluation.
...
PMID:Present use of positive inotropic drugs in heart failure. 248 Apr 92

Recent advances in our knowledge of heart failure have shown that both a central and a peripheral factor are involved in this syndrome. Therefore, the ideal drug should combine the properties of a positive inotropic agent with those of a peripheral vasodilator; many drugs recently introduced into clinical practice have been shown to present both of these features, and the term "inodilators" has been used to characterize them. Inodilators can be further classified on the basis of their mechanism of action, i.e., phosphodiesterase inhibitors, and sympathomimetic and dopaminergic drugs. Phosphodiesterase inhibitors include bipyridine, imidazolone, and benzimidazole derivatives, which present potent inotropic and vasodilatatory actions. Despite their favorable acute effects, long-term studies have often yielded controversial, and sometimes disappointing, results as their chronic administration seems often to be associated with untoward effects and, above all, a poor prognosis. Sympathomimetic agonists act by stimulation of beta-receptors, with a consequent increase of myocardial contractility and peripheral vasodilation. Differently from the parenteral drugs (e.g., dobutamine), the oral agents present many important shortcomings including central nervous system effects, increased myocardial oxygen consumption, tachyarrhythmias, and, above all, development of tolerance during chronic administration. Dopaminergic drugs possess a unique pharmacologic profile since they add to the adrenergic stimulation their selective action on dopaminergic receptors. Dopamine is still one of the most useful drugs for the treatment of acute heart failure; the two oral drugs that more closely resemble its actions are levodopa and ibopamine. The administration of levodopa to patients with heart failure can induce a significant hemodynamic improvement that is maintained during chronic therapy. Ibopamine has been widely shown to cause a significant hemodynamic improvement in patients with heart failure. Its effects can be ascribed to a moderate increase of myocardial contractility accompanied by peripheral and renal vasodilatatory actions. This drug can also counteract some of the neurohumoral mechanisms (e.g., sympathetic stimulation and aldosterone secretion) that are activated in heart failure. These features can explain the favorable results that have also been recently obtained after the chronic administration of ibopamine.
...
PMID:Clinical pharmacology of inodilators. 248 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---