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)

Heart transplantation is a widely accepted therapy for end-stage myocardial failure in adults. However, few centers have experience in the treatment of newborns and children. The management of these children from the anesthesiologic viewpoint is demonstrated in our first 10 patients. Ages ranged from 5 days to 5 years; weights ranged from 2900 gm to 16 kg. The children suffered from hypoplastic left heart syndrome (n = 5) or cardiomyopathy (n = 5). Eight patients had to receive catecholamines (dobutamine) before surgery. In neonates cardiopulmonary bypass (CPB) with hypothermic cardiac arrest at 18 degrees C was used; in the older children continuous CPB at 24 degrees to 28 degrees C was performed. Inotropic support during and after weaning from CPB was necessary in all patients who received dobutamine (range, 2 to 10 micrograms/kg/min), epinephrine (range, 0.03 to 1.0 microgram/kg/min), or both. The phosphodiesterase inhibitor enoximone (1.0 mg/kg) was administered to five patients. Prostaglandin E1 was given to four patients, and it was necessary to give additional tolazoline to two patients. Heart transplantation is a challenge for anesthesiologists during the prebypass period as well as during the weaning and early postbypass periods. More experience is necessary to optimize the anesthetic management of these children.
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PMID:Anesthesia in pediatric heart transplantation. 138 52

Enoximone, a phosphodiesterase-inhibitor, is a potent inotropic vasodilator agent that causes a marked improvement in hemodynamics in patients with congestive heart failure. The acute effects of oral enoximone on rest and exercise hemodynamics, ejection fraction, aerobic metabolism, exercise capacity, and arrhythmias were studied in 11 patients with moderate to moderately severe dilative cardiomyopathy after 8 days of enoximone (100 mg tid) in addition to baseline therapy (diuretics and digitalis). The cardiac index increased from 2.44 +/- 0.45 to 2.72 +/- 0.50 l/min/m2 (p less than 0.01) at rest and from 4.00 +/- 0.96 to 4.75 +/- 0.95 l/min/m2 (p less than 0.005) during exercise. Pulmonary wedge pressure decreased from 16.8 +/- 7.3 to 12.5 +/- 6.5 mmHg (p less than 0.005) at rest and from 28.2 +/- 8.0 to 24.5 +/- 10.3 mmHg (p less than 0.05) during exercise. Systemic vascular resistance decreased from 1608 +/- 243 to 1495 +/- 300 dynes*sec*cm-5 (p less than 0.05) at rest and from 1152 +/- 155 to 1027 +/- 236 dynes*sec*cm-5 (ns) during exercise. The anaerobic threshold, which was recorded simultaneously, increased from 13.2 +/- 2.7 to 15.5 +/- 2.5 ml/kg/min VO2 (p less than 0.02). The radionuclide ventriculography ejection fraction improved from 21.7 +/- 5.0 to 28.1 +/- 9.1% (p less than 0.01) during exercise; the changes at rest were not significant (20.8 +/- 6.2 vs 25.8 +/- 8.4%). Exercise tolerance showed an increase of 16% (492 +/- 133 to 573 +/- 135 sec, p less than 0.005). The resting heart rate remained unchanged (81.8 +/- 13.4 vs 81.8 +/- 11.9). Interestingly, 24-h Holter monitoring revealed more or new repetitive arrhythmias in 9/11 patients.
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PMID:Short-term effects of oral enoximone on hemodynamics, exercise capacity, anaerobic threshold, and arrhythmias in congestive heart failure. 171 70

Treatment of patients with heart failure due to major ventricular systolic dysfunction should aim not only at symptomatic but also at prognostic improvement. If correction of the underlying problem is not possible, treatment should slow down the progression of cardiac failure and eliminate triggers for sudden cardiac death due to electromechanical dissociation or arrhythmias. In every patient with chronic congestive heart failure screening for myocardial ischemia and complete revascularization is mandatory, if possible. In patients with coronary artery disease and diminished systolic function, beta-blockade may improve prognosis by reducing ischemic events and sudden cardiac death. The incidence of life-threatening arrhythmias in patients with heart failure may be reduced by eliminating facilitating factors like electrolyte disturbances, altered autonomic tone and raised intracardiac pressure rather than by antiarrhythmic medical treatment itself. One of the most important prognostic aspects in treatment is the interference with the development of the cardiomyopathy of overload, uniformly observed in chronic congestive heart failure. Modification of mechanical and neuroendocrine stimuli may postpone myocardial hypertrophy and interstitial hyperplasia as a consequence of altered gene expression. Early treatment with ACE inhibitors and in certain patients with betablockers are the most promising strategies to delay the progression of the disease. In contrast, positive inotropic drugs, including digitalis and phosphodiesterase inhibitors, do not improve prognosis. Calcium antagonists should also be used with restriction, as Verapamil and Diltiazem, but also Nifedipine may adversely affect the outcome in congestive heart failure patients.
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PMID:[Prognostic aspects in the treatment of chronic heart insufficiency]. 173

The efficacy of enoximone (EN), a new phosphodiesterase inhibitor, was studied in 24 patients (pts.) with end-stage cardiac disease due to dilative cardiomyopathy (21 pts.) or coronary heart disease (3 pts.). All pts. admitted for urgent transplantation or mechanical circulatory support demonstrated advanced cardiac failure unresponsive to conventional pharmacotherapy. Despite maximal catecholamine and vasodilator therapy the cardiac index averaged 2.08 l/min per m2, the pulmonary capillary wedge pressure (PCWP) 24 mmHg, and the systemic vascular resistance (SVR) 1450 dyn* s* cm-5. In addition to the previous sympathomimetic medication EN was administered as a bolus injection of 1 mg/kg followed by a continuous infusion of 4 to 10 micrograms/kg/min. In all but 4 non-responding pts., who eventually died, clinical and hemodynamic conditions improved significantly within 4 h: CI increased from 2.08 to 3.1 l/min/m2, PCWP dropped from 24 to 17 mmHg, and SVR decreased from 1450 to 950 dyn* s* cm-5 (all p less than 0.05). After initial improvement, 9 pts. experienced acute hemodynamic and clinical deterioration leading to implantation of a biventricular-assist device (Berlin Heart) in 6 pts., while 3 pts. died of irreversible cardiogenic shock. However, of the remaining 15 pts., who demonstrated sustained hemodynamic improvement, 11 could be weaned off their adrenergic medication and remained on oral EN (1.0 to 1.5 mg/kg TID). Three pts. received heart transplants within 8 to 12 weeks; 7 pts. were still on the waiting list at the end of the study, and 1 pt. died after withdrawal of oral EN.2
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PMID:[Enoximone as pharmacologic "bridging" to heart transplantation]. 183 94

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.
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PMID:[Oral enoximone therapy as a therapeutic bridging before heart transplantation]. 214 96

Enoximone, a relatively new type III phosphodiesterase (PDE III) inhibitor with combined positive inotropic and vasodilating properties, was used as a pharmacological bridge to heart transplantation in a patient with severe dilatative cardiomyopathy (ejection fraction 11-13%), who developed cardiogenic shock refractory to conventional therapy with catecholamines and vasodilators. Enoximone led to an 88% increase in cardiac index (from 1.6 to 3.0 l/min.m2). Despite a noticeable rise in heart rate, stroke index increased by 57%. Systemic vascular resistance decreased by 48% without any relevant change in mean arterial pressure. Cardiac filling pressures remained high. Oxygen transport doubled and oxygen extraction ratio decreased by 10%. Apart from a decrease in arterial oxygen tension (from 15.8 to 12.8 kPa [119 to 96 mm Hg]), no other side effects were noted. Withdrawal of catecholamine therapy did not cause any relevant haemodynamic changes. Although complications arose from an uncontrolled septic state, orthotopic heart transplantation was performed with success 74 hours after initiation of enoximone therapy. As the PDE III inhibitor enoximone exerts its potent inotropic and vasodilating effects without requiring adrenergic receptor activation, it may be used as an alternative to mechanical support in patients who develop cardiogenic shock resistant to catecholamines while awaiting heart transplantation.
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PMID:[Enoximone as an alternative to mechanical circulatory support prior to heart transplantation]. 252 33

The major determinants of myocardial oxygen consumption (MVO2) were examined in the isolated, servo-regulated, canine heart in which coronary perfusion pressure, heart rate, ventricular volume and pressure could be individually monitored and controlled. We found that the integral of systolic wall force and the time derivative of systolic force development were major determinants of MVO2, Net MVO2, seen in response to increments in contractility (dobutamine) and heart rate, were the result of the relative increments in each of these determinants. Additional studies were performed to assess the heart's metabolic reserve and aerobic limit (i.e., before the onset of lactate production). We found that with increments in left ventricular work, mediated by increments in filling volume, heart rate, and contractility (dobutamine), myocardial lactate production could be induced, but was dependent on the level of coronary perfusion pressure. When the aerobic limit of the myocardium was exceeded, its performance declined and pulsus alternans appeared. In patients with cardiomegaly and advanced heart failure given the phosphodiesterase inhibitors enoximone and piroximone we did not observe a rise in MVO2 or the appearance of lactate production in the majority of patients. When patients with documented idiopathic (dilated) cardiomyopathy and marked heart failure received hemodynamically significant doses of dobutamine alone or in combination with amrinone, there again was no evidence of lactate production or a rise in MVO2, while a marked improvement in ventricular function was noted. Thus, these agents served to improve the efficiency of the dilated failing heart. Hence we would conclude that in most cases, the dilated failing heart has an adequate metabolic reserve. It performance, and indeed its efficiency, can be improved with pharmacologic agents having positive inotropic properties without adversely altering myocardial energetics.
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PMID:Myocardial energetics: experimental and clinical studies to address its determinants and aerobic limit. 281 57

In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 microM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found: 1. Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres. 2. During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles. 3. In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment. 4. Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts. Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over "classical" cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.
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PMID:Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533. 282 79

The hemodynamic and myocardial energetic changes due to pulsus alternans were investigated by left and right heart catheterization and by oxygen consumption measurements in three patients with dilative cardiomyopathy. In all three patients, pulsus alternans developed after intravenous administration of the phosphodiesterase inhibitor enoximone. Following enoximone (Patients 1/2/3), left ventricular peak systolic pressure was reduced, in the respective patients, from 100/103/115 mmHg (normal beat) to 91/96/94 mmHg (strong beat) and further to 59/80/85 mmHg (weak beat); left ventricular end-diastolic pressure was reduced from 24/23/22 mmHg (normal beat) to 5/10/6 mmHg (strong beat) and further to 3/7/4 mmHg (weak beat). Cardiac output increased by an average of 16%. Heart rate increased by an average of 12%. Stroke work (during pulsus alternans mean between strong and weak beats) did not change (less than 5%) in any of the three patients. Arterial-coronary-sinus oxygen content difference decreased by 5%/13%/22, respectively. Myocardial oxygen consumption per beat decreased in Patient 1 by 8%, in Patient 2 by 8% and remained unchanged in Patient 3. It is concluded that pulsus alternans occurred in consequence of alternating systolic performance. The alternation in systolic performance most probably resulted from a disturbance in excitation-contraction coupling induced by enoximone. The pronounced reduction of left ventricular preload following administration of enoximone may have augmented further the differences between the strong and the weak beat. A disturbance in myocardial oxygen metabolism was ruled out as the cause of pulsus alternans in these patients.
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PMID:Hemodynamics and myocardial oxygen metabolism of pulsus alternans in patients with dilative cardiomyopathy. 295 30

Experimental cardiomyopathy was produced by isoprenaline (2 x 80 mg/kg sc daily for 2 days). The degree of myocardial damage was evaluated histopathologically. In the damaged cardiac muscle the incorporation of 14C-adenine was impaired, the adenylate cyclase activity was diminished and the total contents of cAMP and 14C-cAMP formed from intracellular 14C-adenine metabolism were reduced. No significant changes in the activity of phosphodiesterase were found. This indicates that cAMP synthesis is impaired as a result of decreased utilization of the ATP pool formed from exogenous adenine in the cardiac muscle damaged by isoprenaline.
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PMID:Incorporation of 14C-adenine to cyclic 3',5'-AMP of cardiac muscle in isoprenaline-induced experimental cardiomyopathy. 626 91


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