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)

Annual mortality from congestive heart failure ranges from 15% to 60%, depending on the severity of the left ventricular damage and underlying disease. Most controlled trials have been too small to detect any beneficial effect on survival from the newer vasodilator and inotropic drugs. However, the results of two recent studies strongly suggest that some vasodilator drugs improve prognosis. In one study, a hydralazine-nitrate combination reduced 2-year mortality by 34%, while in another study, enalapril, in addition to diuretics, digitalis, and directly acting vasodilators, reduced 1-year mortality by 31%. Thus far no large studies have been published with the new phosphodiesterase-inhibiting agents. Although preliminary reports of large-scale trials did not demonstrate changes in survival rate, they have been shown to improve well-being in class III-IV congestive heart failure patients.
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PMID:Therapeutic advances in heart failure. 315 50

We compared the acute hemodynamic effects of intravenous nitroprusside (NTP), a pure vasodilator, to those of intravenous MDL-17,043 (MDL), a phosphodiesterase inhibitor with inotropic and vasodilator effects, in 12 patients with chronic refractory congestive heart failure (CHF). Intravenous NTP was infused and titrated to achieve optimal hemodynamic effects, whereas MDL was given intravenously in 0.5 mg/kg increments every 10 to 15 minutes until no further increase occurred in cardiac output or until a maximum cumulative dose of 4.5 mg/kg had been given. Both NTP and MDL reduced pulmonary capillary wedge pressure (27 +/- 5 to 15 +/- 6 and 29 +/- 3 to 15 +/- 7 mm Hg, respectively; both p less than 0.0001), systemic vascular resistance (2173 +/- 1137 to 1118 +/- 306 and 1805 +/- 425 to 956 +/- 235 dynes-sec-cm-5, respectively; both p less than 0.0002), mean arterial pressure (85 +/- 18 to 69 +/- 14 and 83 +/- 15 to 75 +/- 16 mm Hg respectively; both p less than 0.05), and increased cardiac index (1.7 +/- 0.4 to 2.6 +/- 0.4 and 1.8 +/- 0.2 to 3.3 +/- 0.5 L/minute/m2, respectively; both p less than 0.05) without an overall significant change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative acute hemodynamic effects of intravenous sodium nitroprusside and MDL-17,043, a new inotropic drug with vasodilator effects, in refractory congestive heart failure. 315 82

MDL-17,043, a newly synthesized imidazole derivative, has been shown to manifest both inotropic and peripheral vasodilating properties in experimental animals and to be effective when administered orally. Although MDL-17,043 has been demonstrated to inhibit cyclic adenosine monophosphate (AMP) phosphodiesterase activity in vitro, whether its inotropic activity derives from increased myocellular levels of cyclic AMP is not yet known. After intravenous administration of MDL-17,043 to seven patients with severe congestive heart failure (CHF) at the time of cardiac catheterization, the rate of left ventricular (LV) pressure rise increased almost immediately from a control of 878 +/- 161 to a peak of 1010 +/- 217 mm Hg/sec (p less than 0.01), while cardiac index tended to increase but not significantly. Subsequently, as mean aortic pressure decreased from 86.4 +/- 15.9 at control to 75.6 +/- 16.4 mm Hg (p less than 0.01), cardiac index rose from 1.87 +/- 0.35 at control to 2.30 +/- 0.27 L/min/m2 at peak effect (p less than 0.01), while pulmonary capillary wedge pressure fell from 23.7 +/- 5.1 to 13.1 +/- 4.6 mm Hg (p less than 0.01). Concomitantly, the rate of LV pressure rise returned to control value. Thus, intravenous administration of MDL-17,043 improves myocardial contractility and LV performance in patients with severe CHF. This manifest improvement in LV performance most probably results from both the positive inotropic and direct vasodilating effects of MDL-17,043.
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PMID:Effects of a new cardiotonic agent, MDL-17,043, on myocardial contractility and left ventricular performance in congestive heart failure. 316 Feb 28

The hemodynamic and clinical effects of parenteral and oral CI-930, a new phosphodiesterase type III inhibitor with combined vasodilator and inotropic properties, were studied in 12 patients with severe congestive heart failure refractory to therapy including captopril. The maximum response to dobutamine was also determined. Intravenous CI-930 increased cardiac index from 1.73 +/- 0.48 to 2.38 +/- 0.55 L/min/m2, and reduced pulmonary capillary wedge pressure from 19.2 +/- 7.9 to 12.5 +/- 6.4 mm Hg, mean right atrial pressure from 7.5 +/- 6.3 to 3.6 +/- 4.0 mm Hg, and systemic vascular resistance from 2288 +/- 860 to 1711 +/- 611 dynes . sec . cm-5 (p less than 0.001 for all). Heart rate and mean systemic arterial pressure were unchanged. The increment in cardiac index produced by dobutamine was higher than for CI-930, 2.68 +/- 0.55 vs 2.38 +/- 0.55 L/min/m2, p less than 0.001. However, reduction in pulmonary capillary wedge pressure tended to be less with dobutamine, 15.7 +/- 7.9 vs 12.5 +/- 6.4 mm Hg (NS). Hemodynamic benefits of oral CI-930 were equivalent to that of the parenteral drug. Duration of action was 9 to 12 hours. Chronic therapy resulted in subjective improvement in approximately 50% of patients. Exercise capacity, assessed by maximum oxygen consumption, was unchanged, 8.4 +/- 3.3 vs 9.8 +/- 3.4 ml/kg/min (NS). No overt laboratory manifestations of toxicity were observed.
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PMID:CI-930, a new cardiotonic and vasodilating agent: hemodynamic comparison to dobutamine and long-term clinical effects. 317 74

Piroximone (MDL 19,205), a new phosphodiesterase inhibitor with positive inotropic and vasodilating properties, was administered orally to 12 patients with severe congestive heart failure (NYHA class III to IV). After a mean dose of 1.7 +/- 0.4 (SD) mg/kg, cardiac index increased from 2.0 +/- 0.5 to 3.0 +/- 0.6 liters/min/m2 while pulmonary wedge pressure decreased from 23 +/- 6 to 15.6 +/- 7 mm Hg and systemic vascular resistance from 1520 +/- 370 to 1000 +/- 320 dyne-sec-cm-5. Mean arterial pressure was slightly reduced from 80 +/- 13 to 75 +/- 11 mm Hg and forearm blood flow increased by 79% (all p less than .01). Eleven patients were selected for long-term treatment. Two patients received a heart transplant soon after the treatment was started. The remaining nine patients were followed for a mean of 5.6 months (range 2 to 10). Severe congestive heart failure recurred in eight of these nine patients, resulting in the death of three patients within 4 months. The remaining six patients underwent repeat hemodynamic evaluation 2 months after the initiation of the treatment. A short-term hemodynamic response to the drug in this group demonstrated that piroximone retains its circulatory effect during continuous therapy. Nevertheless, three more patients of this group died within 8 months and two required heart transplants. Of the nine patients receiving long-term treatment, only one had sustained subjective improvement and increased exercise capacity. Therefore long-term therapy with piroximone did not appear to benefit patients with severe congestive heart failure. A drug-related deterioration of their clinical status cannot be excluded.
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PMID:Persistent hemodynamic effects without long-term clinical benefits in response to oral piroximone (MDL 19,205) in patients with congestive heart failure. 351 Jul 78

Hemodynamic response after intravenous and oral administration of a new phosphodiesterase inhibitor, CI-914, was studied in 13 patients with severe congestive heart failure. Comparable significant increases in cardiac index of 26% (p less than 0.01) and 19% (p less than 0.02) after intravenous and oral administration were observed. Systemic vascular resistance, right atrial and pulmonary artery wedge pressure decreased significantly after intravenous drug administration. Although similar changes occurred after oral administration, they were not statistically significant. Peak CI-914 plasma concentration occurred 2.3 +/- 2.2 hours after oral drug administration and exhibited measurable hemodynamic effects for up to 10 to 12 hours. Seven of the 13 patients received long-term oral CI-914 for as long as 12 weeks and exhibited an improvement in New York Heart Association functional class and exercise capacity. Five patients died with progressive heart failure, 1 patient died suddenly and 1 died of sepsis. The drug was well tolerated and appears to have potential as a cardiotonic agent.
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PMID:Hemodynamic effects of a new type III phosphodiesterase inhibitor (CI-914) for congestive heart failure. 351 61

The rationale for the use of vasodilating agents in the treatment of congestive heart failure is to reverse the systemic vasoconstriction that characterises patients with this disorder, and which may further limit cardiac performance. Nitrates were the first vasodilators used, followed by arterial vasodilators (hydralazine, minoxidil), alpha-adrenergic blockers (prazosin, trimazosin) and, more recently, calcium antagonists, ACE inhibitors, beta-agonists and phosphodiesterase inhibitors. The choice of vasodilator should be based on consideration of overall benefit-risk profiles. Consideration of pharmacological action together with classification of patients into haemodynamic subsets has been used as a basis from which to initiate vasodilator therapy. However, such a classification may not lead to a logical choice of drug and there is no evidence to suggest that patients so selected do better when given long term treatment with peripherally specific drugs than with agents that are not tailored to pretreatment haemodynamic variables. Moreover, changes in central haemodynamics after administration of specific vasodilator drugs may differ from those expected on the basis of their presumed actions on the peripheral vasculature. Dosage requirements are difficult to predict with many vasodilator drugs. Traditionally, such requirements have been established by titrating vasodilating drugs to achieve an arbitrarily defined haemodynamic response. However, there is little correlation between haemodynamic end-points and clinical efficacy in patients with heart failure, and short and long term haemodynamic responses to vasodilator drugs are not necessarily related. Drug-specific haemodynamic and clinical tolerance occurs during the course of treatment with all vasodilator drugs; the extent and frequency with which it develops differs between agents. Tolerance is thought to arise from a reduction in drug receptor affinity and/or density or activation of counter-regulatory forces (mainly neurohormonal) that limit the magnitude of vasodilatation that can be achieved. Development of tolerance to a single agent does not usually preclude efficacy of other agents. ACE inhibitors have been associated with a relatively low incidence of tolerance. This may relate to their natriuretic effect and ability to decrease the degree of neurohormonal activation, actions not shared by other vasodilators. Tolerance is the principal reason for failure of prazosin and nitrates as therapeutic agents in severe chronic heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of vasodilator therapy in the treatment of severe chronic heart failure. 355 90

CI-930, a new type III phosphodiesterase inhibitor, was evaluated for treatment of refractory congestive heart failure. The hemodynamic, pharmacokinetic and clinical response to the drug was determined in 10 patients. At the peak plasma concentration after intravenous CI-930, cardiac index increased from 2.0 to 2.7 liters/min/m2 (p less than 0.002), pulmonary artery wedge pressure decreased from 26 to 17 mm Hg (p less than 0.001) and systemic vascular resistance decreased from 1,999 to 1,471 dynes cm-5 (p less than 0.05). Heart rate and blood pressure did not change significantly. Similar changes were observed with oral CI-930. Peak CI-930 plasma concentration occurred 1.2 +/- 0.8 hours after oral administration. Beneficial hemodynamic effects were sustained 12 to 18 hours after the oral dose. The sustained hemodynamic effects observed after oral administration appear to be related to an active metabolite of CI-930 that has prolonged duration of action and slow washout. The drug was well tolerated and has potential for treatment of congestive heart failure.
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PMID:Hemodynamic, pharmacokinetic and clinical response to CI-930 in congestive heart failure due to ischemic or dilated cardiomyopathy. 357 54

The phosphodiesterase inhibitor CI-930 hydrochloride exerts a positive inotropic and vasodilator effect in experimental animals. The acute hemodynamic and hormonal effects of intravenous CI-930 were studied in 9 patients with severe congestive heart failure. At 60 minutes of drug infusion, there was an increase in cardiac index (2.7 +/- 0.9 vs 2.0 +/- 0.7 liters/min/m2, p less than 0.01) and positive dP/dt (1,390 +/- 470 vs 1,100 +/- 300 mm Hg/s, p less than 0.02). Additionally, there were decreases in mean systemic arterial (78 +/- 16 vs 86 +/- 15 mm Hg, p less than 0.01), mean right atrial (5 +/- 3 vs 9 +/- 4 mm Hg, p less than 0.02), mean pulmonary arterial (27 +/- 11 vs 37 +/- 9 mm Hg, p less than 0.01) and LV end-diastolic (19 +/- 8 vs 28 +/- 6 mm Hg, p less than 0.01) pressures. Heart rate did not change (97 +/- 17 vs 97 +/- 22 beats/min). The inotropic response correlated significantly (r = 0.70, p less than 0.05) with the dose of CI-930. Plasma renin activity did not change significantly (from 16 +/- 9 to 23 +/- 15 ng/ml/hour), nor did plasma norepinephrine or arginine vasopressin levels. The plasma atrial natriuretic peptide level decreased (from 153 +/- 97 to 83 +/- 35 pg/ml, p less than 0.02). These findings suggest that intravenous CI-930 hydrochloride is a useful therapeutic agent in congestive heart failure and that its use does not appear to further activate potentially deleterious hormonal systems.
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PMID:Acute hemodynamic and hormonal effects of CI-930, a new phosphodiesterase inhibitor, in severe congestive heart failure. 359 91

A patient with end-stage congestive cardiomyopathy had progressive hemodynamic deterioration while awaiting orthotopic heart transplantation. Attempts to support cardiovascular function by high-dose dobutamine infusions were complicated by life-threatening cardiac arrhythmias. The addition of the noncatecholamine inotropic agent, amrinone, improved ventricular performance, enabling reduction of the dose of dobutamine and resolution of the cardiac arrhythmias. Beta receptor stimulation by dobutamine combined with phosphodiesterase inhibition by amrinone may additively or synergistically augment cardiac function despite severe congestive heart failure and also have an adrenergic "sparing effect."
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PMID:Augmentation of cardiac function in end-stage heart failure by combined use of dobutamine and amrinone. 373 11


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