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

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.
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PMID:Clinical pharmacology of inodilators. 248 42

Enoximone is a positive inotropic agent belonging to the group of phosphodiesterase F-III inhibitors. The drug was tested in 34 patients uncontrolled by sympathomimetic drugs and referred to our department for urgent heart transplantation or circulatory assistance. After insertion of a Swan-Ganzgatheter and a radial artery catheter for haemodynamic monitoring, enoximone was administered as a 15-minute intravenous bolus injection of 1 to 2.5 mg/kf every 8 hours, in addition to sympathomimetic agents. Clinical and haemodynamic improvement was observed after thirty minutes in 30 patients. The cardiac index rose from 1.82 to 2.67 l/min/m2 and the pulmonary wedge pressure fell from 30.8 to 18.9 mmHg. Systemic arterial resistance decreased from 2170 to 1520 dyn. s. cm-5, and pulmonary resistance from 5.5 to 4.6 Wood units (p less than 0.01 for all values). Four patients had no haemodynamic improvement and were put on circulatory assistance, using a Jarvik 7 total artificial heart in 3 of them and heterotopic circulatory assistance in one. After clinical investigation for contra-indication to heart transplantation, and as their improved haemodynamic status permitted, 12 of the 30 patients were considered suitable (group B) for heart transplantation. Transplantation was performed within a week of admission in 11 patients without any need for mechanical assistance. One of the group B patients who required implantation of a Jarvik 7 artificial heart died after 12 hours of assistance. Eighteen patients were considered unsuitable for transplantation (group A) and treated medically.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Enoximone and the therapeutic strategy in patients awaiting emergency cardiac graft]. 252 34

Beta-adrenergic sympathomimetic agents such as dobutamine and dopamine, and phosphodiesterase inhibitors such as amrinone, milrinone, and enoxamone, exert a direct positive inotropic effect upon the myocardium by causing an increase in cyclic AMP levels. The phosphodiesterase inhibitors also exert a substantial direct vasodilator effect. Both the sympathomimetic agents and the phosphodiesterase inhibitors can be of value in the acute, short-term management of myocardial failure. At present, the use of these agents for long-term therapy of congestive heart failure is unproven, and remains investigational.
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PMID:Positive inotropic/vasodilator agents. 256 61

Thus far, all attempts to stimulate melatonin synthesis by beta-adrenergic receptor agonists in the Syrian hamster pineal gland have failed. Neither a wide range of dosages of isoproterenol (0.5 mg/kg to 24 mg/kg), nor prolonged treatment with norepinephrine, the natural neurotransmitter, increased N-acetyltransferase (NAT) activity or melatonin production. In the present study, the administration of isoproterenol at night was likewise ineffective in advancing or enhancing the normal nightly melatonin peak. Also, we did not find a delayed effect 7 or 8 h after the administration of the drug. Furthermore, we tested the idea of coneurotransmitters such as octopamine or dopamine being possibly necessary for stimulation, but could not find any effect of these substances on melatonin synthesis. In addition, a parasympatholytic agent, atropine, did not increase the responsiveness to sympathomimetic agents. Administration of a phosphodiesterase inhibitor was also ineffective in stimulating NAT activity. On the other hand, isoproterenol did retard the drop in NAT and melatonin after lights-on at night, indicating that beta-receptors are involved in maintaining elevated melatonin levels.
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PMID:Pharmacological studies on the regulation of N-acetyltransferase activity and melatonin content of the pineal gland of the Syrian hamster. 300 27

There has been an active search recently for non-glycoside, non-sympathomimetic positive inotropic agents. Phosphodiesterase inhibitors inhibit the breakdown of cyclic AMP, leading to an increase in intracellular cAMP concentration, and can be expected to enhance the force of myocardial contraction. The methylxanthines exert such an action in vitro; the situation in vivo is more complex, due to their manyfold actions. Phosphodiesterase F-III is relatively specific for cAMP degradation; the new phosphodiesterase inhibitors may act specifically by inhibiting this enzyme. Phosphodiesterase inhibitors with combined inotropic and vasodilatory action include amrinone, which is no longer in widespread use due to its pronounced side-effects, milrinone, which is much better tolerated and has shown promising results in recent large-scale trials, and sulmazole which has been withdrawn due to toxic effects in rodents. Other drugs are still under investigation. Of importance is the relative role of the inotropic versus dilatory action of these drugs. A salutory effect on resting haemodynamics, does not necessarily imply improved exercise haemodynamics. The pharmacokinetic profile of these drugs is also of interest. The clinical benefits should be sustained and the side-effects should not outweigh the beneficial actions of these drugs.
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PMID:Non-receptor-mediated inotropic drugs. 304 98

The beta-adrenoceptor agonists have become the cornerstone of bronchodilator therapy. These agents are "functional" or "physiologic" antagonists that actively relax airway smooth muscle through a cyclic-AMP (cAMP)-mediated decrease in myoplasmic Ca2+ content. Hence, unlike specific receptor antagonists, the sympathomimetics should reverse bronchoconstriction regardless of the mediator(s) involved. Indeed, one of the primary beneficial attributes of beta-adrenoceptor agonists is their inhibitory activity against a wide range of bronchoconstrictors. As successful as the sympathomimetic bronchodilators have been, they are not without liabilities. These liabilities include: 1) cardiovascular and skeletal muscle side effects, 2) an inherent subsensitivity of the patient population to beta-adrenoceptor agonists, 3) the development of tolerance, and 4) loss of efficacy during severe asthmatic episodes. These limitations are not specific for individual agents but are shared by all beta-adrenoceptor agonists. A significant improvement in the pharmacotherapy of asthma would be obtained by identifying novel bronchodilators devoid of one or more of the aforementioned liabilities. The development of isozyme-selective phosphodiesterase (PDE) inhibitors is one promising approach toward this goal. Interest in PDE inhibition as a therapeutic target has been renewed by the realization that PDEs exist in multiple isoforms and that the distribution of these isoforms varies significantly among tissues. This information, coupled with the recent synthesis of PDE inhibitors selective for several of the isozymes, raises the possibility of breeding organ-selectivity into this class of compounds. Results from preliminary experiments with isozyme-selective PDE inhibitors have helped to identify appropriate drug targets in airway smooth muscle. These early studies suggest that the synthesis of novel isozyme-selective PDE inhibitors not only may provide tools with which to understand the biologic function of various PDE isozymes, but may also lead to the development of improved therapeutic agents.
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PMID:Action of mediators on airway smooth muscle: functional antagonism as a mechanism for bronchodilator drugs. 305 35

Inotropic drugs are widely used before, during and after cardiac surgery. Besides the old well known inotropic drugs, new sympathomimetic drugs and phosphodiesterase inhibitors are available. They can be used alone or in combination. The choice of drug is difficult to make and depends, for one part, on the side-effects of each drug. Before surgery, they are required for patients who present with cardiogenic shock while waiting for emergency repair of their lesion. During surgery, inotropic drugs are used before, during and after using cardiopulmonary bypass. After surgery, they are used to treat low cardiac output states. A decision algorithm is suggested, but it is modified by personal clinical experience, aetiological patterns and pharmacological data. Therapeutic doses must be adjusted according to haemodynamic data. Physiological controls are required, such as venous return and heart rate. Mechanical assistance devices must not be forgotten, especially after myocardial reperfusion and weaning from extracorporeal circulation.
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PMID:[Indications for inotropic agents in cardiac surgery]. 336 9

Treatment of heart failure comprises the use of diuretics, vasodilators and inotropic substances. Unloading of the heart and the circulation in hydropic states is classically achieved with diuretics. The retention of salt and water in chronic heart failure requires chronic treatment with diuretics. This mode of treatment is basic to all forms of hydropic heart failure. Inotropic substances such as digitalis glycosides, sympathomimetic amines or phosphodiesterase inhibitors have certain disadvantages: Inotropic stimulation increases energy demand of the working heart muscle. Most of the substances used today increase energy consumption inordinately, thereby decreasing economy of myocardial contraction. This aspect calls for caution in the application of these substances in chronic heart failure, although they seem indispensable (sympathomimetic amines) in acute hypotensive failure and shock. Digitalis glycosides, basically suited for longterm treatment, exert only mild inotropic effects. In addition inotropic stimulation brings with it arrhythmogenic effects. All inotropic substances can induce ventricular arrhythmias already at therapeutic levels. Vasodilating substances have found increasing acceptance as a particularly useful and safe group of drugs for the treatment of heart failure. Nitrates: With the different nitrate compounds and nitrate preparations an effective venodilation with preload reduction can safely be achieved. At higher doses, arteriolar also dilatation can be induced. Although tolerance may be a problem with chronic application, this can be avoided with prudent dosing. The strong venodilating property makes these drugs together with their rapid onset of action ideally suited for the treatment of acute heart failure with pulmonary congestion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Treatment of heart failure: status of therapy with vasodilator agents]. 343 15

Retrospective studies have shown that patients with severe chronic heart failure who receive long-term treatment with positive inotropic agents have a high mortality rate, but in the absence of controlled trials it remains unclear whether the high incidence of fatal cardiovascular events in these patients is related to treatment or to the severity of the underlying disease. Most of the evidence that suggests a detrimental effect of positive inotropic therapy on survival remains circumstantial. The pooling of data from long-term studies of patients after an acute myocardial infarction suggests that use of digitalis may be associated with an unfavorable effect on survival. The prolonged administration of intravenous or oral catecholamines is associated with a high mortality rate, which may not be seen in similar patients treated conventionally. The presence of intrinsic sympathomimetic activity appears to neutralize the benefits of beta-blockade during the first year after an acute myocardial infarction; treatment with such agents after the first year may increase mortality. Long-term treatment with phosphodiesterase inhibitors is associated with a high mortality rate, which exceeds that reported in earlier years with vasodilator therapy. Nevertheless, most of these studies of positive intropic agents were not performed to evaluate the issue of survival and did not randomly assign patients to treatment groups. Hence, we do not know that the patients entered into these studies were truly comparable to their proposed control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Survival in congestive heart failure during treatment with drugs with positive inotropic actions. 355 3

Intrathecal administration of norepinephrine (NE) and alpha adrenergic agonists in rats with chronic spinal catheters produced a significant elevation of the nociceptive threshold as measured by hot plate and tail flick. The intrathecal NE effect was dose-dependent and antagonized in a competitive fashion by pretreatment with phentolamine (alpha antagonist) but not by propranolol (beta antagonist). Intrathecal administration of isoproterenol (beta agonist) did not alter the nociceptive threshold. Effective doses of intrathecal NE did not produce demonstrable motor effects. Doses 20 times greater than the maximum analgesic dose produced marked weakness of the hindlimbs and tails. The intrathecal NE effect was not antagonized by intrathecal papaverine of bradykinin (vasodilators) or mimicked by angiotensin-II (vasoconstrictor). The intrathecal NE effect was not altered by intrathecal administration of subconvulsant doses of either picrotoxin (gamma-aminobutyric acid antagonist) or strychnine (glycine antagonist) or by i.p. administration of either naloxone (opiate antagonist) or methysergide (serotinin antagonist). The nociceptive threshold was significantly decreased 1 week after intrathecal administration of 6-hydroxydopamine, which depleted spinal cord NE by 85%. Intrathecal administration of tyramine (indirectly acting sympathomimetic amine) produced an elevation of the nociceptive threshold in a control group of animals but was less effective in animals pretreated with intrathecal 6-hydroxydopamine. The tyramine effect was antagonized by intrathecal phentolamine. Intravenous administration of aminophylline (phosphodiesterase inhibitor) did not potentiate the intrathecal NE effect. The relative antinociceptive potencies of alpha adrenergic agonists after intrathecal administration were: l-norepinephrine = dl-epinephrine greater than dl-alpha-methyl norepinephrine greater than clonidine greater than or equal to l-phenylephrine greater than or equal to 3,4-dihydroxytolazoline greater than or equal to oxymetazoline. The relative potencies of intrathecally administered alpha antagonists in antagonizing the intrathecal NE effect were: phentolamine greater than phenoxybenzamine greater than tolazoline greater than or equal to yohimbine.
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PMID:Spinal cord pharmacology of adrenergic agonist-mediated antinociception. 611 Jul 67


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