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)

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and not mediated by stimulation of adrenergic receptors, histaminic receptors, cholinergic receptors, Ca++-adenosine triphosphatase, Mg++-adenosine triphosphatase, adenyl cyclase or inhibition of Na+, K+-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Pharmacology of enoximone. 295 61

Enoximone, a phosphodiesterase inhibitor, is a potent inotropic vasodilator agent that causes a marked improvement in systemic hemodynamics in patients with severe chronic congestive heart failure. Cardiac index, stroke volume index and stroke work index increase, and there is a significant decrease in pulmonary capillary wedge pressure. Left ventricular dP/dt increases, despite a decrease in arterial pressure and systemic vascular resistance and without any significant change in heart rate, indicating a positive inotropic effect. A marked decrease in systemic vascular resistance indicates that decreased left ventricular outflow resistance resulting from peripheral vasodilation also contributes to improvement in left ventricular function. In some patients, left ventricular end-diastolic volume increases despite a marked decrease in pulmonary capillary wedge pressure, suggesting an improvement in apparent left ventricular compliance, which may also be contributory to improved left ventricular function.
...
PMID:Potential mechanisms of improved left ventricular function with enoximone in severe congestive heart failure. 295 66

Atrial natriuretic peptide (ANP) induces potent diuretic/natriuretic, vasorelaxing and aldosterone inhibitory effects. Increased plasma levels in congestive heart failure (CHF) have been reported. The aim of this study was to investigate plasma immunoreactive ANP (ir-ANP) levels during acute treatment of CHF. Seven patients with CHF underwent cardiac catheterization. Ir-ANP plasma levels were followed up to two h after administration of an orally given phosphodiesterase inhibitor (Milrinone); a substance with positive inotropic and peripheral vasodilating properties. In all patients cardiac output increased and cardiac filling pressures decreased markedly. Initially high ir-ANP plasma levels decreased. Our patients did not have an increased blood volume. It is concluded that plasma ir-ANP levels in the pulmonary artery rapidly decrease when atrial pressure is reduced. These data suggest that atrial pressure is the major determinant for release of ir-ANP in man and that the ability to respond quickly to changes in cardiac filling pressures is maintained in patients with severe CHF. Plasma ir-ANP levels may also become useful as an index of the degree of heart failure and serve as a tool in monitoring response to drug therapy.
...
PMID:Atrial natriuretic peptide during acute treatment of congestive heart failure. 296 29

Twelve patients with congestive heart failure underwent a double-blind, placebo-controlled study for the purpose of examining the central and regional hemodynamic effects of first-dose (1 and 2 mg/kg) oral enoximone, a new phosphodiesterase III inhibitor. Enoximone augmented cardiac output, generally through a positive chronotropic response. Indices of left ventricular contractility, specifically stroke volume, delta P/delta t, fractional shortening rate, and the duration of the preejection period, were only modestly enhanced by enoximone. At 2 mg/kg, systemic vascular resistance fell below baseline values without affecting systemic blood pressure; these parameters were not altered by the 1 mg/kg dose. Both pulmonary artery pressure and pulmonary vascular resistance dropped below baseline and below placebo control for the 2 mg/kg dose. Enoximone at 2 mg/kg lowered right and left heart filling pressures below baseline. Examination of regional hemodynamic responses to both doses demonstrated a reduction in limb vascular resistance and an increase in limb blood flow proportional to the concomitant increase in cardiac output. Renal and hepatic-splanchnic blood flow and vascular resistances were not altered by enoximone. First-dose oral enoximone (1 and 2 mg/kg) alters hemodynamics in heart failure by predominant vasodilatation, particularly of limb-musculoskeletal and pulmonary vascular beds, some positive chronotropism, and modest positive inotropism.
...
PMID:Central and regional hemodynamic effects of oral enoximone in congestive heart failure: a double-blind, placebo-controlled study. 296 46

Some biochemical and pharmacological properties of a novel, potent inhibitor of cyclic AMP phosphodiesterase, N-cyclohexyl-N-methyl-4-(7-oxy-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one) butyramide (RS-82856), were investigated. RS-82856 selectively inhibits the high affinity form of cyclic AMP phosphodiesterase (type IV) isolated from human platelets (Ki = 0.5 nM) with only weak effects on both the nonspecific and cyclic GMP-sensitive phosphodiesterases. The inhibitor reduces both maximum velocity and substrate affinity of the type IV enzyme. This mixed pattern of partial competitive and noncompetitive inhibition was also obtained with one of the two high affinity forms of phosphodiesterase found in dog heart (Ki = 0.75 nM). Of several human and dog tissues examined, RS-82856 exhibits marked selectively for the platelet high affinity enzyme. It also has significant inhibitory effects on cardiac membrane-bound phosphodiesterase. RS-82856 inhibits the aggregation of human platelets in response to adenosine 5'-diphosphate (IC50 = 0.11 microM) in vitro and is active ex vivo for at least 2 hr following oral administration (10 mg/kg) to rhesus monkeys. Administration of RS-82856 to instrumented, anesthetized dogs by either intravenous or intraduodenal routes increases cardiac contractile force and reduces afterload. These data suggest that RS-82856 may be useful as an agent to increase cardiac output in the treatment of congestive heart failure.
...
PMID:A potent and selective inhibitor of cyclic AMP phosphodiesterase with potential cardiotonic and antithrombotic properties. 301 20

Imidazo[4,5-b]pyridines, such as AR-L57, AR-L100 and AR-L115 (Vardax), have been of interest as inotropic agents for the management of congestive heart failure. Although it has been presumed that their activities derive from inhibition of phosphodiesterase, it is now apparent that similar structural analogs possess surprisingly diverse pharmacologies and mechanisms of action. AR-L100 increased the contractile state of cat papillary muscles in a concentration-dependent manner; these effects were not blocked by either alpha, beta or H2-receptor antagonists. To determine whether the contractile responses resulted from intracellular cyclic AMP accumulation, the cardiotonic actions of AR-L100 were assessed in the presence of carbachol. Muscarinic receptor stimulation did not alter inotropic responses to AR-L100; in addition, AR-L100 did not potentiate the inotropic actions of isoproterenol. These results imply that cyclic AMP is not involved in the cardiac responses to this agent. AR-L100 inhibited Na+,K+-adenosine triphosphatase activity of either canine kidney or cardiac sarcolemmal vesicles. Inhibition of this enzyme paralleled inotropic responses in vitro; that is, in papillary muscle, the EC50 for contractility was 11.5 microM compared with an IC50 for inhibition of Na+,K+-adenosine triphosphatase of 8 microM. By contrast, the IC50 for inhibition of phosphodiesterase (isozyme III) was 280 microM. AR-L100 also inhibited sodium pump activity in intact cat papillary muscles. Concentrations of 30 and 100 microM AR-L100 resulted in 13 and 45% decreases in ouabain-sensitive 86Rb+ uptake determined at 3 Hz. In anesthetized dogs, AR-L100 increased contractility but did not alter either heart rate or mean arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Molecular basis for the in vitro and in vivo cardiotonic activities of AR-L100. 302 55

Congestive heart failure is a clinical syndrome with inadequate cardiac output and increased venous pressure, characterized by hyperfunction of the sympatho-neuro-endocrine system, favoring maximal vasoconstriction in non-essential organs and retention of salt and water. Identification of the cause of heart failure and its correction is the best treatment. The suppression of precipitant factors is also essential. Traditionally the treatment of congestive heart failure is based on diuretics, restriction of salt intake, and digitalis. The conventional vasodilators are effective in the short term, but they have a marked tendency to tachyphylaxis. The inhibitors of angiotensin-converting enzyme are, through their specific action on neuro-endocrine dysregulation, the most important advance in recent years. Of the non-glycosidic inotropic agents used in severe heart failure, the new inhibitors of phosphodiesterase need further testing. In certain cases, permanent synchronous pacing has to be considered.
...
PMID:[Pathophysiologic aspects and modern treatment of congestive heart failure]. 302 12

The bipyridine derivative amrinone is a specific phosphodiesterase III blocking agent. In vitro and in vivo studies show a dose-dependent increase in myocardial contractility induced by amrinone. In patients with congestive heart failure, the inotropic and vasodilator effects of amrinone contribute to cardiac improvement. When amrinone is used, the increase in myocardial oxygen consumption due to increased contractility is offset by the reductions in preload and afterload. In hearts with very high wall tension, myocardial oxygen consumption may even decrease with amrinone. Amrinone therapy is not accompanied by significant increases in heart rate. Tachyphylaxis has not been observed. The elimination half-life ranges between 2.5 and 3.5 h. A large quantity of amrinone is excreted unchanged, and therefore in cases of renal impairment the possibility of cumulation exists. The main adverse reaction of amrinone is a reversible thrombocytopenia induced by a dose-dependent decrease in platelet survival time. Therefore, frequent platelet counts are necessary when amrinone is administered. Numerous studies in patients with chronic congestive heart failure confirmed the beneficial hemodynamic effects of amrinone. Experience in the treatment of acute perioperative heart failure with amrinone are still limited, but the present results are encouraging; an additive effect of amrinone to catecholamines seems especially promising in the therapy of severe postoperative low-cardia-output syndrome.
...
PMID:[Amrinone (Wincoram)--a new positive inotropic and vasodilator agent]. 304 13

Milrinone is a bipyridine derivative of amrinone, with approximately 10 to 75 times greater positive inotropic potency, and separate direct vasodilatory properties. As with amrinone, the relative importance of these properties to treatment of congestive heart failure still remain controversial. The mode of action of milrinone appears to be due in part to selective inhibition of a specific cardiac phosphodiesterase with a subsequent increase in intracellular cyclic adenosine monophosphate and alteration in intracellular and extracellular calcium transport. Clinical experience has involved both short and long term treatment of a limited number of patients with moderate to severe congestive heart failure refractory to conventional therapy. Milrinone has usually been administered as intravenous bolus doses (12.5 to 75 micrograms/kg) and/or continuous intravenous infusion (0.5 microgram/kg/min), or orally (30 to 40 mg/day in divided doses). Milrinone rapidly improves cardiac performance by enhancing myocardial contractility, and by decreasing systemic vascular resistance (afterload), left ventricular filling pressure (preload), and pulmonary arterial pressure. Exercise performance improvement occurs with enhancement of left ventricular performance but without a significant increase in myocardial oxygen consumption or significant decrease in mean arterial pressure. Milrinone has been compared with dobutamine, nitroprusside and captopril in preliminary short term studies in patients with severe congestive heart failure. Milrinone significantly increased stroke work index and decreased left ventricular filling pressure compared to nitroprusside. When compared with dobutamine, both drugs improved cardiac index (to a similar degree), but milrinone significantly reduced right atrial pressure, pulmonary capillary wedge pressure and left ventricular end-diastolic pressure. One small study suggests that short term effects of intravenous milrinone may be superior to those of oral captopril, and it appears that the addition of captopril to milrinone therapy may produce a synergistic haemodynamic effect. Preliminary long term studies suggest that tolerance to the haemodynamic effects of milrinone does not occur, and that the drug is well tolerated and without the thrombocytopenic effects, fever and gastrointestinal complications observed with amrinone. However, it has not been demonstrated that milrinone improves the prognosis of the disease or the overall mortality and its propensity to produce arrhythmias has not been fully agreed upon.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Milrinone. A preliminary review of its pharmacological properties and therapeutic use. 305 25

Pharmacokinetics is the study of the effect that the body has on drug absorption, distribution, metabolism and excretion. The pharmacokinetics of a specific drug are assessed by the volume of distribution, bioavailability, clearance and elimination half-life. Elimination half-life is directly related to the volume of distribution and inversely related to clearance. Any 1 or more of these parameters may be altered by physiological changes such as ageing, or disease states such as congestive heart failure. Congestive heart failure is associated with hypoperfusion to various organs including the sites of drug clearance, i.e. the liver and kidneys. It also leads to organ congestion as seen in the liver and gut. The main changes in drug pharmacokinetics seen in congestive heart failure are a reduction in the volume of distribution and impairment of clearance. The change in elimination half-life consequently depends on whether both clearance and the apparent volume of distribution change, and the extent of that change. Pharmacokinetic changes are not always predictable in congestive heart failure, but it seems that the net effect of reduction in the volume of distribution and impairment of clearance is that plasma concentrations of drugs are usually higher in patients with congestive heart failure than in healthy subjects. The changes in pharmacokinetics assume importance only in the case of drugs with a narrow therapeutic ratio (e.g. digoxin) and some of the antiarrhythmics such as lignocaine (lidocaine), procainamide and disopyramide. This necessitates reduction in both the loading and maintenance doses. Prolongation of the elimination half-life leads to delay in reaching steady-state, and therefore dose increments must be made more gradually. Plasma concentration measurements of the drugs concerned are a good guide to therapy and help to avoid toxicity. Pharmacokinetic changes are of less importance in the case of drugs with immediate clinical response, e.g. diuretics and intravenous vasodilators such as nitrates and phosphodiesterase inhibitors. The dose in the latter group can be titrated to the desired effect. Not all adverse reactions to drugs that may occur in heart failure are the result of alterations in pharmacokinetics; rather, some may be due to important drug interactions. An interaction may occur directly e.g. reduction of renal clearance of digoxin by captopril and quinidine; or indirectly, e.g. through diuretic-induced hypokalaemia, which exacerbate arrhythmias associated with digoxin and antiarrhythmics such as quinidine and procainamide.
...
PMID:Clinical pharmacokinetics in heart failure. An updated review. 306 53


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

---