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)

Venodilatation may be an important property in drugs used to treat heart failure. Deductions about venous tone from standard hemodynamic studies may be misleading since filling pressures may be reduced by improved left ventricular function. To study the venodilator properties of drugs, we have modified a radionuclide blood pool method and shown that venous volume is increased by 10% after glyceryl trinitrate but is unchanged after the arteriolar dilator hydralazine. In patients with congestive cardiac failure, the calcium channel blocker, felodipine, causes a marked reduction in systemic vascular resistance and left ventricular filling pressures, but venous volume remains unchanged. In a similar group of patients comparable arterial and central effects are seen after the administration of captopril, but venous volume increases by 16%, and this increased venous volume is sustained after 3 months of long-term treatment. Milrinone has been used to treat both acute and chronic heart failure. As expected of a phosphodiesterase inhibitor, it exhibits inotropic properties in animals and humans and also causes arterial vasodilatation. We have studied its effects on venous tone in 10 patients with severe heart failure (New York Heart Association classes III to IV). Milrinone was given intravenously at a loading dose of 50 micrograms/kg followed by an infusion of 0.5 micrograms/kg/min. After treatment, cardiac index, which was measured by thermodilution, increased from 1.8 +/- 0.48 to 2.3 +/- 0.65 L/min/m2 (p less than 0.001); pulmonary artery wedge pressure fell from 23 +/- 6 to 11 +/- 5 mm Hg (p less than 0.001); and systemic vascular resistance index decreased from 4296 to 3168 dynes.sec.cm-5/m2 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Modulation of venous tone in heart failure. 203 25

The benzimidazol analogue BM14.478 is a phosphodiesterase inhibitor with both vasodilator and positive inotropic properties. Hemodynamic parameters and plasma hormone levels of 8 patients (1 female, 7 male) with chronic congestive heart failure NYHA Classes II-IV (1 patient with coronary artery disease, 7 patients with primary dilated cardiomyopathy) were assessed before and until 6 h after the intravenous application of 1.0 mg BM14.478. There was a significant decrease of mean pulmonary artery pressure (28 +/- 11 vs. 23 +/- 11 mmHg; p less than 0.05), mean right atrial pressure (8.6 +/- 5.2 vs. 5.0 +/- 4.7 mmHg; p less than 0.02), and systemic vascular resistance (1651 +/- 484 vs. 1206 +/- 252 dynes.s.cm-5; p less than 0.05) as early as 10 min after injection of BM14.478. Pulmonary vascular resistance also was reduced (128 +/- 86 vs. 61 +/- 39 dynes.s.cm-5, 30 min after injection; p less than 0.02). Simultaneously there was a significant increase of cardiac index (2.3 +/- 0.7 vs. 3.1 +/- 0.8 l.min-1.m-2, 10 min after injection; p less than 0.02), and stroke volume index (28.8 +/- 11.7 vs. 33.9 +/- 8.5 ml.min-1.m-2; 30 min after injection; p less than 0.05). Although mean heart rate did not change significantly, some patients reacted with a transient increase. There was also a slight but insignificant increase of the double product. No serious side effects were observed. The hemodynamic improvement was followed by a delayed reduction of plasma levels of epinephrine (51 +/- 20 vs. 41 +/- 21 pg/ml; p less than 0.02; 30 min after injection) and atrial natriuretic peptide (229 +/- 283 vs. 121 +/- 168 pg/ml; p less than 0.05; 1 h after injection). Mean levels of plasma norepinephrine, however, did not change significantly and individual responses showed large variations, which could not be predicted by the behavior of the hemodynamic parameters. Three of eight patients (2 of these with elevated baseline filling pressures) even showed a marked increase of plasma norepinephrine levels after BM14.478. Response of plasma renin activity and plasma vasopressin levels to BM14.478 also was heterogeneous. According to the results of this study, acute administration of the phosphodiesterase inhibitor BM14.478 has an immediate beneficial hemodynamic effect in patients with severe congestive heart failure by reducing both preload and afterload, and by increasing cardiac index and stroke volume. However, this improvement of hemodynamic parameters is not necessarily accompanied by a favorable short-term response of plasma hormones, and therefore does not allow any conclusions on survival of these patients.
...
PMID:Hemodynamic and neuroendocrine response to acute administration of the phosphodiesterase inhibitor BM14.478 in patients with congestive heart failure. 204 89

A multicenter double-blind, randomized, placebo-controlled trial of oral enoximone, a phosphodiesterase inhibitor, was conducted in 102 outpatients (50 receiving enoximone and 52 receiving placebo) with moderate to moderately severe congestive heart failure. All were on a long-term regimen of digoxin and diuretics without vasodilators and converting enzyme inhibitors. Symptom score was obtained, and exercise testing was performed monthly for 4 months. There were no differences between groups in symptoms or exercise duration at the end of 4 months. A subgroup undergoing analysis of oxygen consumption with measurement of anaerobic threshold during exercise showed an increase (p less than 0.05) in anaerobic threshold at 1 month with enoximone. (2.7 +/- 0.8 ml O2/kg/min) compared with placebo (-0.8 +/- 1.2 ml O2/kg/min). This improvement was not sustained at 4 months (0.5 +/- 1.7 ml O2/kg/min with enoximone and 0.2 +/- 1.5 ml O2/kg/min with placebo). The dropout rate was significantly higher (p less than 0.02) with enoximone (46%) than with placebo (25%). Adverse effects other than death were slightly, but not significantly, higher with enoximone (32%) than with placebo (22%). During therapy, five deaths occurred in the enoximone group, and none occurred in the placebo group (p less than 0.05). Two deaths were sudden, two were from progressive congestive heart failure, and one was from acute myocardial infarction. With intention-to-treat analysis and inclusion of patients who were removed from therapy because of lack of study drug effect, 10 deaths occurred in the enoximone group, and three occurred in the placebo group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group. 214 15

In severe chronic congestive cardiac failure the physician has the choice of two families of positive inotropic agents, the direct sympathomimetics and the phosphodiesterase inhibitors. The aim of the study was to compare the efficacy and tolerance of enoximone and dobutamine in this indication. Twenty patients with severe chronic cardiac failure with a cardiac index of less than 2.2 l/min/m2 and pulmonary capillary pressure of over 20 mmHg were randomised into two groups in an open trial. One group received enoximone 50 micrograms/kg/min for 30 minutes then 10 micrograms/kg/min and the other received dobutamine 10 micrograms/kg/min. The two groups were comparable. Results were analysed 12 hours after starting therapy, well after the loading dose of enoximone and before the appearance of tolerance to dobutamine. Neither drug caused a significant change in heart rate or mean blood pressure. The pressure-rate product did not increase significantly with enoximone (+9.2% NS) in contrast with the dobutamine group in which a significant elevation was observed (+23.5%, p less than 0.05). The cardiac index increased with enoximone (+61.0%, p less than 0.01) and with dobutamine (+32.1%, p less than 0.02). This resulted mainly from an increase in the systolic index (+45.5%, p less than 0.05 with enoximone and +30.1%, p less than 0.05 with dobutamine). Pulmonary capillary pressure and total systemic resistance decreased with enoximone (-29.1%, p less than 0.001 and -36.7%, p less than 0.05 respectively) and with dobutamine (-23.4%, p less than 0.001 and -20.7%, p less than 0.05 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:[Enoximone/dobutamine comparison in chronic congestive cardiac insufficiency with low cardiac output]. 214 31

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration. Its pharmacological effects are due to the inhibition of the type IV phosphodiesterase: positive inotropism, vasodilatation and positive chronotropic action. The efficacy of enoximone in improving cardiovascular function in patients with congestive heart failure has been documented in many studies, but not in studies having mortality as the main end-point. In conclusion, enoximone cannot be safely proposed yet for the chronic treatment of congestive heart failure in association with classic management, until convincing evidence of its long-term benefit/risk profile will be given.
...
PMID:[Enoximone]. 214 96

A 58-year-old male patient with end-stage cardiomyopathy suffered from cardiac decompensation under parenteral catecholamine medication. Oral therapy with 450 mg Enoximone daily achieved recovery after 4 weeks, so that an orthotopic cardiac transplantation could be performed. The postoperative outcome was uneventful. Selective phosphodiesterase-inhibitors help to fill a therapeutic gap in the management of catecholamine-refractory heart failure.
...
PMID:[Oral enoximone therapy as a therapeutic bridging before heart transplantation]. 214 96

A series of 6-benzoxazinylpyridazin-3-ones was prepared and evaluated for inhibition of cardiac phosphodiesterase (PDE) fraction III in vitro and for positive inotropic activity in vivo. 6-[3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2,3,4,5-tetrahydro-5 - methylpyridazin-3-one (bemoradan) was found to be an extremely potent and selective inhibitor of canine PDE fraction III and a long-acting, potent, orally active inotropic vasodilator agent in various canine models. Additional benzoxazin-6-yl and -8-yl compounds were also prepared. Altering the pyridazinone substitution from the 6-position to the 7-position produced a 14-fold increase in the iv cardiotonic potency (ED50) from 77 to 5.4 micrograms/kg while substitution at the 8-position reduced potency. Methyl substitution at various sites in the molecule was also examined. Positive inotropic activity was maintained for between 8 and 24 h after a single oral dose (100 micrograms/kg) of bemoradan in dogs, thus making it one of the most potent and long-acting orally effective inotropes yet described. Bemoradan is currently under development as a cardiotonic agent for use in the management of congestive heart failure.
...
PMID:6-Benzoxazinylpyridazin-3-ones: potent, long-acting positive inotrope and peripheral vasodilator agents. 215 10

The functional importance of abnormalities in the myocardial beta-adrenergic receptor (BAR) pathway of patients with congestive heart failure (CHF) is not known. To address this issue, the inotropic, chronotropic, and lusitropic responses to BAR stimulation were studied in patients with CHF and in patients without cardiac disease. To evaluate inotropic responsiveness, dobutamine was infused directly into the left main coronary artery. The maximum inotropic response, as assessed by measurement of left ventricular +dP/dt, was markedly reduced in patients with CHF; however, the concentration-response curve for the effect of dobutamine was not shifted relative to that of normal subjects. The magnitude of the impairment in the inotropic response to intracoronary dobutamine was inversely related to resting plasma norepinephrine. Although there was no relation between resting plasma norepinephrine and any measure of hemodynamic function, the improvement in pump function that occurred with intracoronary dobutamine resulted in a rapid decrease in plasma norepinephrine. Preinfusion of the phosphodiesterase inhibitor, milrinone, into the coronary artery resulted in a significant increase in the response to intracoronary dobutamine. To evaluate chronotropic responsiveness, the heart rate responses to a graded infusion of isoproterenol and during maximal exercise on a cycle ergometer were determined. The isoproterenol dose causing a 25 beat/min increase in heart rate (ISO25) was significantly higher in patients with CHF than in normal subjects. Likewise, the heart rate at peak exercise was significantly reduced in patients with CHF, despite similar levels of plasma norepinephrine at peak exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:In vivo studies of myocardial beta-adrenergic receptor pharmacology in patients with congestive heart failure. 216 96

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

Previous studies have demonstrated the high prevalence of frequent and complex ventricular arrhythmias in patients with severe congestive heart failure. It has been claimed that these arrhythmias are independent risk factors of prognosis. Moreover in severely depressed left ventricular function frequent and repetitive arrhythmias may deteriorate the hemodynamic situation. Recent clinical studies have drawn increasing attention to the possibility that the desired therapeutic effect of Class I antiarrhythmic agents may be complicated by their ability to aggravate the arrhythmia or to provoke new arrhythmias. These "proarrhythmical effects" were more frequent in patients with life-threatening arrhythmias and in those with severely depressed left ventricular function. Prevention trials with Class I antiarrhythmic agents have failed to show beneficial effects on the arrhythmia profile and on the prognosis of those patients. On the other hand, it is now well recognized that the incidence of cardiac death can be reduced by the use of ACE-inhibitors in this patient population. Accordingly, there is evidence of a reduced incidence of complex ventricular arrhythmias during treatment with these drugs in some of the patients with congestive heart failure. The influence of digitalis on the arrhythmia profile and the cardiac mortality in these patients is still a matter of debate. On the other hand, there is evidence that newer positive inotropic agents such as phosphodiesterase-inhibitors rather increase the number of arrhythmias and the prevalence of sudden cardiac death in this patient population.
...
PMID:[How are tachycardic cardiac arrhythmias modified by therapy of congestive heart failure?]. 219 21


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

---