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)

Inotropic support is often required for post-operative management of patients following mitral valve operation. The use of positive inotropes is limited by tolerance development and increase in myocardial oxygen demand. We have compared i.v. enoximone (E) (group E, n = 13), a recently developed phosphodiesterase (PDE) inhibitor, to the conventional i.v. therapeutics dopamine (D) and glyceroltrinitrate (G) in patients following mitral valve operation. The two groups were comparable in terms of physical and pre-operative haemodynamic data. Haemodynamic measurements including cardiac index (CI) determinations were recorded for the first 18 h post surgery in both groups. Group E received a bolus of 1 mg.kg-1 E followed by 4-20 micrograms.kg-1.min-1 (mean = 5 +/- 2 micrograms.kg-1.min-1) for 14 h according to therapeutic requirements, while group D received dopamine (4-10 micrograms.kg-1.min-1, mean = 3.8 +/- 1.9 micrograms.kg-1.min-1) and glyceroltrinitrate (0.5-5 micrograms.kg-1.min-1; mean = 4 +/- 2 micrograms.kg-1.min-1). Adrenaline was added if the MAP was below 60 mmHg or the CI was below 2.5 in both groups (range 50-500 ng.kg-1.min-1; mean E = 0.7 +/- 2 ng.kg-1.min-1; mean D = 2 +/- 2.8 ng.kg-1.min-1). Bolus injection of E resulted in a rise in CI from 2.6 to 3.21.min-1.m-2 (P less than 0.05) within 30 min, followed by a further rise to a maximum of 3.51.min-1.m-2 6 h post bolus. Termination of the E drip resulted in a drop of CI to baseline values (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enoximone, a post-operative inodilator in patients following mitral valve operation: a prospective and controlled study. 153 88

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.
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PMID:Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure. 170 Feb 5

The new phosphodiesterase-III inhibitor (PDI) enoximone is a non-catecholamine, non-glycoside cardiotonic agent with concomitant vasodilating properties. It has proved beneficial in patients with severe chronic heart failure. The influence of enoximone i.v. on hemodynamics was investigated during cardiac surgery under various conditions. METHODS. A randomized series of 60 patients undergoing elective aorto-coronary bypass grafting were studied. The hemodynamic effects of 0.5 mg/kg enoximone given i.v. as a bolus (30 s) were investigated before anesthesia (n = 10), during anesthesia (n = 10), and during extracorporeal circulation (ECC, n = 10) and compared with those observed in corresponding control groups (n = 10 in each control) of patients who had received saline solution as placebo. Anesthesia was maintained with weight-dependent dosages of fentanyl, midazolam and pancuronium bromide. All patients were invasively monitored by means of a pulmonary artery catheter. Additionally, left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP) and dp/dtmax were measured before the initiation of ECC. During ECC direct vascular effects were investigated with measurement of perfusion pressure and the volume of the oxygenator. RESULTS. Before the induction of anesthesia no significant change in MAP and HR could be observed, whereas CI increased (+20%) and TSR decreased (-24%) significantly. During anesthesia, the injection of enoximone was followed by a significant decrease in MAP only in the 1st min (-17%); baseline level was reached again after 6 min; and HR was slightly increased (+8%). TSR (-31%) and LVEDP (-38%) decreased, whereas CI (+17%) and dp/dtmax (+45%) were increased significantly. During ECC perfusion pressure (-37%) and the volume of the oxygenator (-17%) were significantly decreased, demonstrating direct vasodilating effects on both the arteries and the vein. CONCLUSION. Arterial and venous vasodilation with an increase in myocardial performance (dp/dtmax) resulting in an increase in CI were the predominant hemodynamic effects of enoximone i.v. No arrhythmogenic effects or interactions with the anesthetics used were observed in this study.
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PMID:[Hemodynamic effects of the new phosphodiesterase inhibitor enoximone in heart surgery patients]. 252 51

The mechanism of action of theophylline is still the subject of controversy. Possible mechanisms that have been suggested are inhibition of phosphodiesterase, release of catecholamines, effects on intracellular calcium, and adenosine antagonism. With regard to these aspects, it was the aim of this study to compare sympatho-adrenal responses after theophylline application during different anesthetic techniques. A total of 60 patients scheduled for orthopedic surgery were investigated: they were divided into three groups of 20 patients who received either halothane anesthesia with thiopentone induction, modified neurolept anesthesia with fentanyl and midazolam, or spinal anesthesia with bupivacaine and mepivacaine. Within these three groups, the patients were randomly allocated to a theophylline collective receiving an injection of theophylline, 4 mg/kg body weight and to the control group. Plasma levels of epinephrine and norepinephrine (by HPLC/ECD), glucose, lactate and free glycerol and MAP and HR were determined over a period of 120 min. In all groups, epinephrine levels increased immediately after injection of theophylline; group levels of epinephrine were higher in the theophylline-groups than in controls (P less than 0.0001). A remarkable increase was observed within 60 min. Peak epinephrine concentrations were comparable after single injections of 100 micrograms or infusions of 5 micrograms/min. The norepinephrine increase after theophylline injection was brief and less pronounced. MAP, HR, glucose, lactate and free glycerol were not influenced by theophylline. A comparison of the theophylline patients showed no statistical differences attributable to the different anesthetic techniques.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Sympatho-adrenergic reactions following theophylline administration with the use of various anesthesia technics]. 276 71

During cardiac surgery treatment of deterioration of myocardial function is usually based on catecholamines. Development of selective phosphodiesterase-(PDE-)III-inhibitors seems to be a new aspect in treating myocardial dysfunction. Therefore the hemodynamic effects of the new PDE-inhibitor enoximone were investigated in 20 coronary surgery patients unable to be weaned from extracorporeal circulation (ECC) without pharmacological intervention (MAP less than 60 mmHg, CI less than 2.00 l/min.m2, PCP greater than 15 mmHg). After controlled reperfusion with 2.4 1/min.m2 two groups were separated in a random sequence receiving either 0.5 mg/kg enoximone as a bolus (n = 10), or dobutamine (n = 10, 5 micrograms/kg.min) as perfusion. In the dobutamine-group MAP and CI (-14%) were decreased, while HR was increased significantly (+30%). Application of enoximone was followed by a slight increase in CI (+5%), a significant decrease in TSR while HR remained almost unchanged. PCP, too, differed significantly between the groups (enoximone: -38%; dobutamine: -10%). Ten minutes after weaning from ECC additional pharmacologic therapy (calcium, vasodilators, epinephrine) was necessary in eight dobutamine treated patients in contrast to four patients in the enoximone group (calcium, epinephrine). In patients with impaired myocardial performance during weaning from ECC enoximone seems to be an alternative therapy and is judged to be of some advantage compared to dobutamine application in this situation. The mechanism for improvement appears to be enhanced contractility owing to its positive inotropic effects, as well as a decrease in left ventricular outflow resistance resulting from peripheral vasodilation.
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PMID:[Enoximone, a new phosphodiesterase inhibitor: the spectrum of applications during heart surgery--a comparison with dobutamine]. 297 97

Ventricular arrhythmias and disturbed autonomic control, as reflected by abnormal heart rate variability (HRV), are related to hemodynamic impairment in chronic heart failure (CHF). We investigated the effects of orally (p.o.) administered isomazole, a new phosphodiesterase (PDE) inhibitor with calcium-sensitizing properties, on hemodynamics, ventricular arrhythmias, and HRV and examined a possible interaction between these parameters. Hemodynamic measurements and ambulatory ECG monitoring were performed in 12 patients with stable CHF class III-IV after single doses of isomazole 5-30 mg. Pulmonary wedge pressure decreased after 5, 10, 20, and 30 mg, but cardiac output, (CO) increased only after the higher doses [20 mg, + 20% (p = 0.031)] of isomazole. HR did not change. Mean arterial and pulmonary artery pressure, (MAP, PAP) decreased significantly in the 10- and 20-mg groups [10 mg, -6% (p = 0.035) and -14% (p < 0.001) respectively; 20 mg, -13% (p = 0.047) and -31% (p = 0.006), respectively]. Isomazole did not exert a significant effect on ventricular arrhythmias in the subsequent 24 h after acute dosing. Analysis of HRV showed that rMSSD and pNN50 (parameters of vagal tone) tended to increase after isomazole administration. Normalized high-frequency power during the day increased from 17.4 to 22.3 nu (p < 0.05), whereas low frequency tended to decrease from 52.7 to 48.2 nu (p = 0.06). Acute isomazole administration improves hemodynamics but has no effect on ventricular arrhythmias. The HRV variability data suggest development of an increase in vagal control of HR, parallel to the acute hemodynamic improvement after isomazole. Withdrawal of vagal control of HR in CHF may be a reversible process.
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PMID:Exploratory study of the effects of single doses of isomazole on hemodynamics and heart rate variability parameters in chronic heart failure. 772 57

Renal failure after cardiac surgery using cardiopulmonary bypass (CPB) is well understood for infants, children and adults. The perioperative risk factors after CPB for immature kidneys in newborns are not well known. This retrospective study investigates perioperative risk factors for renal insufficiency in neonates. I) Preoperative: Age; weight, performed angiography, amount of dye used in angiography, renal disease and creatinine. II) Intraoperative: Duration of operation, duration of MAP < 40 mmHg, use of deep hypothermia, in-out fluid balance, duration of CPB, duration of circulatory arrest and cross-clamp time. III) Postoperative: Creatinine, use of catecholamines, use of nitroglycerine (NG) or phosphodiesterase inhibitors (PDI) and additional antibiotics. From Jan. 1990 to Dec. 1994 50 neonates underwent cardiac surgery using CPB (n = 23 transposition of the great arteries; n = 4 pulmonary atresia; n = 6 critical pulmonary stenosis; n = 5 hypoplastic left heart syndrome; n = 3 Ebstein's anomaly; n = 2 interrupted arch with hypoplastic left ventricle; n = 2 single ventricle; n = 1 each: double outlet right ventricle, tricuspid atresia, critical aortic stenosis, rhabdo-myosarkoma, corrected transposition of the great arteries.) Thirty-one patients entered the study. Depending on the postoperative creatinine level two groups (group I: creatinine <1 mg/dl and group II: >1 mg/dl) were created. The diureses between the two groups did not differ. Comparing the patients of group I vs. group II, patients of group I were younger (mean age: 7.7 d. vs. 11.4 d), lighter (mean weight: 3260 g vs. 3430 g), less had angiography (44% vs. 77%), received more dye (mean amount: 14 ml vs. 7 ml), the duration of MAP < 40 mmHg while on CPB was longer (mean duration 3 min vs. 21 min), more patients were operated on using deep hypothermia (55% vs. 27%), the postoperative in-out-fluid balance was more positive (mean balance +413 ml vs. +221 ml), received postop. more frequently high doses of catocholamines and less common NG or PDI, but more often additional antibiotics. The duration of circulatory arrest (mean time: 60 min vs. 55 min) and cross clamp time (mean time: 68 min vs. 65 min) seems not to be a risk factor and vasodilators given simultaneously with catecholamines may have preventive effects on postoperative renal insufficiency. Immature kidneys may play an outstanding role in the susceptibility of damaging factors. Further investigation with a larger number of patients allowing to obtain statistical significant risk factors are required.
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PMID:Renal insufficiency in neonates after cardiac surgery. 883 54

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
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PMID:[New therapy developments in rheumatoid arthritis]. 1175 32

There is growing evidence from neuroimaging and ostmortem studies that severe mood disorders, which have traditionally been conceptualized as neurochemical disorders, are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably cyclic adenosine monophosphate [cAMP] response element binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant potentiating modalities. This suggests that effective treatments provide both trophic and neurochemical support, which serves to enhance and maintainnormal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of refractory depression include N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists. Small-molecule agents that regulate the activity f growth factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising future avenues. The development of novel, nonaminergic-based therapeutics holds much promise for improved treatment of severe, refractory mood disorders.
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PMID:Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. 1270 57

1. The isolated circulatory response to intravenous application of the phosphodiesterase (PDE) inhibitors piroximone and enoximone was studied. 2. In a randomized sequence of 30 male patients undergoing elective aortocoronary bypass grafting either piroximone (0.5 mg kg(-1); n = 10) or enoximone (0.5 mg kg(-1); n = 10) were given during steady state of cardiopulmonary bypass (CPB). A group in which NaCl was given as a placebo served as a control (n = 10). 3. MAP was reduced by piroximone (maximum -23 mm Hg) and enoximone (maximum -18 mm Hg), whereas it increased in the control (+20 mm Hg). Volume of the extracorporeal circuit indicating venous pooling decreased more pronouncedly in the enoximone patients (-440 ml) than in the piroximone group (-300 ml). 4. Laser Doppler flows (LDFs) increased in both PDE-III inhibitor groups with the higher and longer increase in the enoximone-treated patients (LDF-forehead maximum +44%, LDF-forearm maximum +33%). Piroximone-induced increase in both LDFs was less pronounced with respect to both time and degree (LDF-forehead maximum +30%, LDF-forearm +12%). 5. Oxygen consumption (VO2) was significantly higher in the PDE-III inhibitor-treated than in the control patients. 6. Piroximone and enoximone showed significant vasodilatory properties at the arterial and venous side (= 'venous pooling'), from which patients with heart failure would profit. 7. Vasodilation could be observed for a longer period and was more pronounced in the enoximone-treated than in the piroximone patients. Alterations in capillary skin blood flow measured by laser Doppler technique gave evidence for an improvement in nutritive microcirculation, which was slightly more pronounced in the enoximone patients.
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PMID:Circulatory effects of the PDE-inhibitors piroximone and enoximone. 1295 8


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