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)

The inotropic vasodilator, ICI 153,110, a phosphodiesterase inhibitor intended for the treatment of congestive heart failure, was administered to Alderley Park Wistar-derived rats for periods of up to 182 days. Treatment produced hypertrophy of salivary glands, hyperplasia of intestinal mucosa, and dacryoadenitis of the harderian gland. As the functions of these glandular tissues can be modified by factors which alter cyclic nucleotide metabolism, it is postulated that the glandular alterations produced by ICI 153,110 occurred as a result of phosphodiesterase inhibition.
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PMID:Long-term effects of an inotropic phosphodiesterase inhibitor (ICI 153,110) on the rat salivary gland, harderian gland, and intestinal mucosa. 178 Jun 38

The available literature on the evaluation of diastolic function, the importance of diastolic dysfunction in congestive heart failure (CHF), and the effects of therapeutic agents on diastolic dysfunction are summarized. The normal cardiac cycle consists of two components: systole (contraction; ventricular emptying) and diastole (dilation; ventricular filling). Recent studies have shown that 30-40% of patients with CHF have normal systolic function; the majority of these patients have diastolic dysfunction as the underlying disorder. As a result, the role of diastolic dysfunction in CHF is currently an area of interest for researchers. The two primary causes of diastolic dysfunction are left ventricular hypertrophy and ischemic heart disease. Patients with CHF caused by diastolic dysfunction and patients with CHF caused by systolic dysfunction have nearly identical clinical presentations. Therapy with diuretics, vasodilators, angiotensin-converting-enzyme inhibitors, beta-agonists, the partial beta-agonist xamoterol, phosphodiesterase III inhibitors, or calcium-channel blockers may be beneficial in patients with diastolic dysfunction. Therapy with digitalis glycosides would be of no benefit, and could theoretically be detrimental, in patients with predominant diastolic dysfunction. Available data indicate that beta blockers have neither an important beneficial effect nor an important detrimental effect on diastolic function. Continued studies into diastolic dysfunction and the diastolic properties of agents that are used in the treatment of CHF should enhance the understanding of this clinical syndrome and the drugs used to treat it.
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PMID:Diastolic dysfunction in congestive heart failure. 179 21

Beneficial effects of cardiotonic phosphodiesterase inhibitors on congestive heart failure are possibly mediated in part by a reduction of afterload. 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3- pyridinecarbonitrile hydrochloride monohydrate (E-1020, CAS 119615-63-3), a new cardiotonic phosphodiesterase inhibitor was evaluated for its effect on aortic input impedance in eight anesthetized open-chest dogs. First instantaneous aortic pressure and flow under random ventricular pacing before and after E-1020 infusions (10, 30, and 100 micrograms/kg i.v.) were measured. Then aortic input impedance over the frequency range of 0.024 to 20 Hz was estimated using a multichannel autoregressive model. With the infusion of E-1020, aortic input impedance was decreased in the low frequency range (below 0.1 Hz) and shifted leftward in the transitional frequency range (from 0.1 to 2 Hz), while it remained unchanged in the high frequency range (above 2 Hz). Parameterization of the aortic input impedance using a three-element Windkessel model indicated that E-1020 (at a dose of 100 micrograms/kg i.v.) decreased arterial resistance by 35% (p less than 0.01) and increased arterial compliance by 12% (p less than 0.01). It is concluded that E-1020 improves cardiac performance by unloading static and dynamic afterload in addition to its cardiotonic effect.
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PMID:Effects of the new cardiotonic phosphodiesterase inhibitor 1,2-dihydro-5- imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3-pyridine-carbonitrile hydrochloride monohydrate on aortic input impedance. 181 18

Vasodilators have been shown to improve hemodynamics of the failing heart as a short-term effect, and to decrease mortality as a long-term result. We, therefore, studied the effects of vasodilators and inotropic agents on myocardial mechanics and energetics in patients with congestive heart failure New York Heart Association (NYHA) classes II-III. In these patients, who underwent routine heart catheterization, myocardial oxygen consumption was measured using the argon method, and LV pressure and geometry were obtained from LV angiography using a Millar microtipped catheter. All data were analyzed for one single heart beat. The best correlation was found between MVO2/beat and the systolic stress-time integral which considers LV pressure, LV wall thickness, and LV geometry. The relation between MVO2/beat and peak systolic wall stress was less relevant. No correlation was found between MVO2/beat and pressure-volume work, dP/dtmax, and mean velocity of circumferential fiber shortening. The intravenous application of nitroprusside and the ACE-inhibitor benazepril decreased both the systolic stress-time integral and the myocardial oxygen consumption in proportion to each other, indicating unchanged economy of myocardial contraction. In contrast, beta 1-agonists and phosphodiesterase inhibitors increased myocardial oxygen consumption independently of changes in the stress-time integral. In conclusion, vasodilators decrease LV pressure and chamber size and thereby proportionally reduce MVO2/beat. The reduction of energy needed for myocardial contraction may partially explain the long-term effects of the ACE-inhibitors and combinations of vasodilators. Pure inotropic substances, especially beta 1-agonists, increase myocardial oxygen consumption with only minor changes of systolic stress-time integral.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Energetic consequences of substances currently used or recommended for long-term treatment of chronic heart failure. 182 77

For the past several years, the UTAH Cardiac Transplant Program has been investigating the use of enoximone, a phosphodiesterase inhibitor with unique properties, as an oral pharmacologic adjunct to conventional management of severe congestive heart failure in patients awaiting heart transplantation. The goal of this approach is not long-term survival, but the ability to maintain patients comfortably with adequate tissue perfusion until the donor heart becomes available. Enoximone exhibits both positive inotropic and vasodilator characteristics. It appears to be the only agent that produces positive inotropic effects by phosphodiesterase inhibition alone, and its effects appear to last significantly longer than those of beta-adrenergic agonists. The results of the program's clinical experience with 281 patients suggest that inotropic support with low-dose enoximone may be a useful adjunct in the short-term management of patients with severe end-stage congestive heart failure. Almost 25% of patients who had been dependent on intravenous inotropic support were able to be weaned from intravenous therapy and switched to oral enoximone. No acceleration in mortality while patients awaited transplantation was observed. The data also showed an increase in the beta 2-adrenergic receptors and a difference in the beta 1:beta 2-receptor subtype ratio of 56:42 with enoximone, compared with 65:35 in a group of failing control patients who received no enoximone. In addition, the combination of enoximone and beta-adrenergic agonists was not associated with beta-receptor down-regulation.
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PMID:Enoximone as a bridge to heart transplantation: the Utah experience. 183 Feb 22

Hemodynamic measurements were done in 42 patients with congestive heart failure of NYHA classes III and IV after administration of the phosphodiesterase inhibitors amrinone und enoximone. Amrinone decreases mean arterial pressure (-4%), right atrial pressure (-39%), and systemic vascular resistance (-23%), while cardiac index and stroke volume index increase to 27% and 26%, respectively; heart rate is nearly unchanged. Enoximone administration in a dose of 1 mg/kg bw produces an increase in cardiac index of 13%, an increase in heart rate of 12%, and a decrease of systemic vascular resistance of 13%, whereas stroke volume index is unchanged. Enoximone in a dose of 1.5 mg/kg bw increases heart rate (+ 9%), cardiac index (+ 33%), and stroke volume index (+ 21%), and decreases systemic vascular resistance (-26%). The hemodynamic profile of amrinone and enoximone in an equal dose shows only slight differences. Furthermore, phosphodiesterase inhibitors produce an increase of cardiac index (+ 19%) and stroke volume index (+ 17%) in patients with pump failure having already received dopamine and dobutamine.
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PMID:[The hemodynamic profile of amrinone and enoximone in patients with severe heart failure]. 183

This study was designed to compare the positive inotropic properties of enoximone, a cardiac phosphodiesterase III inhibitor, with those of dobutamine in a population of moderate to severe congestive heart failure patients. The end-systolic pressure-volume relationship method was used. In addition, the haemodynamic effects of both drugs were compared. In seven of the 11 patients studied, enoximone induced a significant shift upwards and to the left of the end-ejection pressure/end-systolic volume (EEP/ESV) relation, giving evidence of a true positive inotropic effect. In the remaining patients, improvement in cardiac pump function was observed together with a shift of the EEP/ESV relation along the line of iso-inotropism and appeared to be the result of the vasodilatory effect of the drug alone. Data from nine patients were available for comparison with dobutamine which induced a shift upward and to the left of the EEP/ESV relation in seven patients. At the therapeutic doses chosen, the difference between the inotropic effects of the two drugs was not significant (P = 0.07). Of the three patients available for comparison who did not manifest inotropic response with enoximone, two were also dobutamine 'non-responders': they differed from the 'responder' patients in two respects: they had undergone surgery for correction of valvular disease and had significantly higher pulmonary artery pressures. The haemodynamic measurements confirmed the vasodilatory properties of enoximone; in particular, the fall in ventricular filling pressures was much greater with enoximone than with dobutamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison between the positive inotropic effects of enoximone, a cardiac phosphodiesterase III inhibitor, and dobutamine in patients with moderate to severe congestive heart failure. A study using the end-systolic pressure-volume relationship method. 183 66

Congestive heart failure is an increasingly common patient problem. It is a multisystem disease that involves not only the heart but also the kidneys and neurohormonal systems. Any treatment for heart failure should address depressed contractility and exercise intolerance, as well as control compensatory mechanisms. There are many different approaches to the treatment of congestive heart failure: among the drugs used are diuretics, digitalis compounds, nitrates, calcium channel blockers, beta-blockers, beta-agonists, vasodilators, angiotensin-converting enzyme (ACE) inhibitors and the new phosphodiesterase inhibitors. The therapy usually involves a multiple drug treatment plan to achieve the maximum effect for the patient with the lowest incidence of side effects. Heart failure involves a large spectrum of patients with left ventricular dysfunction, and success at achieving treatment goals with these patients will vary with the severity of that symptom. A major concern is that increasing contractility may further damage the myocardium and shorten the survival of these patients, although there is as yet no evidence of such shortening. The new phosphodiesterase inhibitor drugs are an exciting development in the treatment of heart failure, because they add a dimension to the treatment for patients who are not sufficiently improved by a regimen of digoxin, diuretics and ACE inhibitors. Any new heart failure medication should be able to improve rest and exercise haemodynamics, maintain its benefits when given orally and result in an improved exercise capacity and quality of life, and prolonged survival.
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PMID:Risks and benefits of the treatment of heart failure. Current status. 188 43

A series of 1,2-dihydro-5-imidazo[1,2-a]pyridinyl-2(1H)-pyridonones was synthesized and evaluated for positive inotropic activity, 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2- oxo-3-pyridinecarbonitrile (11a) hydrochloride monohydrate (E-1020) was found to be a potent and selective inhibitor of phosphodiesterase III and a long-acting, potent, orally active positive inotropic agent. Additional imidazo[1,2-a]pyridin-2-yl (3a), -3-yl (16), -7-yl (20) and -8-yl (24a) compounds were also prepared. Altering the pyridine substitution from the 2-position to the 6-position produced a 2-fold increase in the i.v. cardiotonic potency (ED50) from 52 to 23 micrograms/kg, while substitution at the 3-, 7- or 8-position reduced potency. In the 2-positional isomers, introduction of halogen groups enhanced the activity and 3-chloro-1,2-dihydro-5-(6-fluoroimidazo[1,2-a] pyridin-2-yl)-6-methyl-2(1H)-pyridinone (3u) was the most potent (i.v. ED50 11 micrograms/kg) in this series. E-1020 is presently under development for the treatment of congestive heart failure.
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PMID:Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives. 193 78

The therapeutic concepts of congestive heart failure (CHF) are based on an increase in myocardial contractility and a decrease in pre- and afterload. Besides the digitalis glycosides, diuretics and vasodilators such as nitrates, hydralazine, ACE-inhibitors, calcium antagonists or prazosine are used. Furthermore, the so-called inodilators such as phosphodiesterase III inhibitors (amrinone, milrinone), dopaminergic and beta-adrenergic receptor agonists were introduced into therapy. The boone and bane of the different classes of drugs were discussed with respect to their hemodynamic and clinical properties.
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PMID:Review: therapeutic concepts of congestive heart failure. 197 88


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