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)

Paediatric cardiac transplantation (pHTX) has gained widespread acceptance as a therapy in end-stage myocardial failure and some forms of congenital heart disease, particularly hypoplastic left heart syndrome (HLHS). The major problems to the anaesthesiologist in these patients are induction of anaesthesia in infants with HLHS and treatment of pulmonary hypertension in the early post-bypass period. PATIENTS AND METHODS. Anaesthesia for pHTX was performed in 15 children < 1 year of age (4-237 days); 12 suffered from HLHS, 2 from endocardial fibroelastosis, and 1 from dilatative cardiomyopathy. Induction of anaesthesia in patients with HLHS IS a challenge to the anaesthesiologist, as he has to maintain the delicate balance between pulmonary and systemic blood flow. Anaesthesia was induced with fentanyl (10-15 micrograms/kg) and pancuronium (0.2-0.4 mg/kg) and maintained with fentanyl (total dosage 70-100 micrograms/kg). Modification of ventilatory parameters such as FiO2, PaCO2, and airway pressure (PEEP, I:E ratio) was used to influence systemic and pulmonary blood distribution in the pre-bypass period according to changes in haemodynamics (target: O2 saturation approximately 75%-80%, PaCO2 45-50 mmHg). Treatment of pulmonary hypertension in the weaning and early post-bypass period consisted of respiratory (PaCO2 < 30 mmHg) and metabolic alkalinisation (pH 7.45-7.55, BE > +3 mmol/l), the use of prostaglandin E1 (3-6-12 micrograms/kg.h), and the phosphodiesterase inhibitor enoximone (10-15 micrograms/kg.min). Additional positive inotropic support was achieved with dobutamine (5-10 micrograms/kg.min), adrenaline (0.1-0.5 micrograms/kg.min), and/or orciprenaline (0.1-0.2 micrograms/kg.min) and calcium chloride (25-100 mg/kg). RESULTS. Two children died intraoperatively and 1 on the 1st postoperative day from overwhelming pulmonary vascular resistance and right ventricular failure. Three children died between 3 and 4 weeks postoperatively, 1 from cytomegalovirus infection, 1 from sepsis, and 1 from acute rejection. Nine patients survived and are well up to 5.5 years after transplantation. CONCLUSION. Pulmonary hypertension in the weaning and early post-bypass period is the main anaesthesiological problem of pHTX, particularly in children with HLHS. A polypragmatic approach to this problem consisting of alkalinisation, pulmonary vasodilatation, and inotropic support is presented and seems to be effective. Further improvements in concepts of pHTX are limited by the lack of donor organs. Though the experience with pHTX in neonates and infants is growing slowly, it might be a routine procedure from the anaesthesiological point of view within a few years in some selected centres.
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PMID:[Anesthesia for heart transplantation in newborn and suckling infants. Special aspects of the hypoplastic left heart syndrome]. 778 53

When fluid administration is not sufficient to restore hemodynamic stability, inotropic agents may be given to restore the tissue perfusion pressure and to increase oxygen delivery (DO2) to the cells. Dopamine remains the drug of choice in the resuscitation of septic shock but norepinephrine can also have a place in the treatment of profound cardiovascular collapse or severe right ventricular failure. Dobutamine has become the inotropic agent of choice to increase DO2 to the tissues. Unfortunately, the beneficial effects of these agents on the extraction capabilities of the tissues are questionable. The potential of other adrenergic agents (such as dopexamine) or nonadrenergic agents (such as phosphodiesterase inhibitors) is also discussed in this article. Inotropic therapy should be guided not only by measurements of systemic BP but also by repeated assessments of the metabolic function of organs.
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PMID:Inotropic agents. 792 87

Amrinone, a selective phosphodiesterase III inhibitor, has been developed as a nonglycoside, noncatecholamine agent with positive inotropic effect. In this study, we examined the effect of amrinone on human pulmonary arterial strips in vitro to understand its action on human pulmonary circulation. Amrinone (10(-5)-10(-3) g/ml) caused dose-dependent relaxation of human pulmonary arterial strips precontracted with 60 mM KCl. Preincubation with either meclofenamate (3.1 microM), a cyclooxygenase inhibitor, or L-N(G)-nitroarginine (100 microM), a competitive inhibitor of EDRF/NO, failed to inhibit amrinone-induced pulmonary vasodilation. The cyclic AMP (cAMP) levels in the supernatant of the lung vessel homogenates increased after incubation with amrinone (10(-3) g/ml). These findings indicate that amrinone causes vasodilation of human pulmonary artery in vitro, and suggest a possible role for cAMP in the mechanisms of amrinone-induced pulmonary vasodilation. Because it is suggested that amrinone has not only positive inotropic effect but also pulmonary vasodilative effect in human in this study, we speculate that amrinone could be an useful agent for the treatment of an increase in right heart afterload and consequent pulmonary hypertension and right heart failure after lung resection in human.
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PMID:Relaxation of human isolated pulmonary arteries by amrinone. 867 27

Myocardial function is determined by preload, afterload, contractility and heart rate. Pathologic changes of these variables may result in decrease of blood pressure, acute heart failure or cardiogenic shock. Hyperdynamic septic shock is associated with systemic hypotension despite increased cardiac output. Mediators of sepsis induce both myocardial depression and pulmonary arterial hypertension. Moreover, sepsis is characterized by microcirculatory disturbances and dysbalance in regional oxygen delivery and consumption. Severe systemic hypotension is a symptom often requiring catecholamine therapy to restore systemic circulation and to avoid organ damage. As the use of catecholamines is not a causal therapy administration should be limited to an initial measure until correction of the underlying abnormalities can be achieved. Different etiologies of shock as well as diseases requiring specific interventions as pulmonary embolectomy, systemic lysis or coronary angioplasty have to be considered. First line intervention consists of optimizing preload by fluid resuscitation as appropriate and use of dopamine (4-12 micrograms/kg.min) as primary catecholamine to increase contractility and blood pressure. In acute left heart failure inotropic support with dobutamine (4-12 micrograms/kg.min) or epinephrine (0.05-1 microgram/kg.min) may be necessary, frequently combined with a vasodilator (sodium nitroprusside 0.2-5 micrograms/kg.min or nitroglycerine 0.5-2.5 micrograms/kg.min) or phosphodiesterase-III-inhibitor (milrinone 0.3-0.8 microgram/kg.min). In right heart failure norepinephrine is preferred to increase coronary perfusion pressure. Hyperdynamic septic shock with decreased vascular resistance is treated with norepinephrine to restore mean arterial pressure and to improve right ventricular dysfunction induced by pulmonary hypertension.
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PMID:[The basics of catecholamine therapy. 2. A guide to clinical use]. 1076 48

Right ventricular failure after left ventricular assist device implantation sometimes requires additional mechanical right ventricular support. The effectiveness of nitrates, prostaglandin, or nitric oxide inhalation in such cases has already been reported. However, there are few reports on the administration of phosphodiesterase inhibitor for right ventricular failure after left ventricular assist device implantation. We report two patients with right ventricular failure after left ventricular assist device implantation successfully treated with milrinone. Both had residual pulmonary hypertension due to high pulmonary vascular resistance after left ventricular assist device implantation. However, intravenous milrinone caused a significant reduction in pulmonary vascular resistance and an increase in left ventricular assist device flow. Milrinone acts as both an inotropic agent and a direct vasodilator, and thus may avoid the need for mechanical support for right ventricular failure due to residual pulmonary hypertension after left ventricular assist device implantation.
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PMID:Effects of milrinone for right ventricular failure after left ventricular assist device implantation. 1183 45

First reports on the use of inhaled nitric oxide (NO) in patients were published in 1991. These reports confirmed data from animal experiments which suggested a selective vasodilatory effect of inhaled NO in pulmonary vessels. As the main clinical effects, both improved oxygenation and a drop of pulmonary artery pressure despite unchanged arterial pressure were observed. Since then, many studies have evaluated the effects of inhaled NO as well as of other aerosolised vasodilators (e.g. PGI(2), PGE(1), nitrates, phosphodiesterase-inhibitors) in patients with pulmonary hypertension, acute right heart failure and/or life-threatening hypoxemia. However, primary pulmonary hypertension of the newborn (PPHN) is the only indication for which inhaled NO has been clinically approved so far. Although an obvious clinical benefit in outcome from inhaled vasodilators has never been formally documented, good clinical efficacy has resulted in an increasing "off label" use of the concept both in Germany and worldwide, particularly with respect to anaesthesia and intensive care medicine. The present article aims to review both the pathophysiological and pharmacological basis of inhaled vasodilators, to critically reevaluate their potential clinical indications and to give a perspective on future developments in the field.
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PMID:[Inhaled vasodilators]. 1239 20

Chronic obstructive pulmonary disease is one of the commonest causes of morbidity and mortality in the world, and is increasing in prevalence. Current therapies are not very effective, and no current treatment prevents the relentless progression of airflow limitation that characterizes this disease. Smoking cessation is the only strategy that reduces this decline in lung function, and although bupropion is the most effective aid to quitting, more effective treatments of nicotine addiction are needed. The mainstay of treatment is bronchodilators for symptom relief, and inhaled anticholinergics and beta(2)-agonists are useful by reducing hyperinflation of the lungs. A new once-daily inhaled anticholinergic is the most effective bronchodilator, but long-acting inhaled beta(2)-agonists are also useful. Theophylline is used as an additional bronchodilator in more severe patients, and may have some anti-inflammatory action. In contrast, inhaled corticosteroids are poorly effective and do not reduce disease progression, although recent studies with combination inhalers (corticosteroid + long-acting beta(2)-agonist) have shown better effects. Long-term oxygen therapy is needed by patients with pulmonary hypertension and right heart failure. There is a pressing need to develop new classes of therapy, and several new drugs are current in development, including interleukin-8 antagonists, phosphodiesterase-4 inhibitors, protease inhibitors, and antioxidants.
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PMID:Therapy of chronic obstructive pulmonary disease. 1249 36

Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature leading to vasoconstriction and remodeling of the pulmonary arteries. The resulting increase in the right ventricular afterload leads to right ventricular failure and death. The treatment options are limited, expensive and associated with significant side effects. The nitric oxide (NO) pathway in the pulmonary circulation provides several targets for the development of new therapies for this disease. However, the NO pathway is modulated at multiple levels including transcription and expression of the NO synthase gene, regulation of the NO synthase activity, regulation of the production of cyclic guanomonophosphate (cGMP) by phosphodiesterases, postsynthetic oxidation of NO, etc. This makes the study of the role of the NO pathway very difficult, unless one uses multiple complementary techniques. Furthermore, there are significant differences between the pulmonary and the systemic circulation which make extrapolation of data from one circulation to the other very difficult. In addition, the role of NO in the development of pulmonary hypertension varies among different models of the disease. This paper reviews the role of the NO pathway in both the healthy and diseased pulmonary circulation and in several animal models and human forms of the disease. It focuses on the role of recent therapies that target the NO pathway, including L-Arginine, inhaled NO, the phosphodiesterase inhibitor sildenafil and gene therapy.
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PMID:The role of the NO axis and its therapeutic implications in pulmonary arterial hypertension. 1265 55

Primary pulmonary hypertension (PPH) is a rare disorder characterised by raised pulmonary-artery pressure in the absence of secondary causes. Precapillary pulmonary arteries are affected by medial hypertrophy, intimal fibrosis, microthrombosis, and plexiform lesions. Most individuals present with dyspnoea or evidence of right heart failure. Echocardiography is the best non-invasive test to screen for suspected pulmonary hypertension. The discovery of mutations in the coding region of the gene for bone morphogenetic protein receptor 2 in patients with familial and sporadic PPH may help not only to elucidate pathogenesis but also to direct future treatment options. The pathogenesis is not completely understood, but recent investigations have revealed many possible candidate modifier genes. Without treatment, the disorder progresses in most cases to right heart failure and death. With current therapies such as epoprostenol, progression of disease is slowed, but not halted. Many promising new therapeutic options, including prostacyclin analogues, endothelin-1-receptor antagonists, and phosphodiesterase inhibitors, improve clinical function and haemodynamic measures and may prolong survival.
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PMID:Primary pulmonary hypertension. 1273 78

Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.
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PMID:Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. 1469 3


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