Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterase inhibitors that are selective for cAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved, only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular cAMP and ionic calcium. In addition, a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither beta-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides, complementary and synergistic to the actions of catecholamines, and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction, open heart surgery, or infectious or toxic myocarditis), heart failure resulting from right ventricular systolic dysfunction, and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute positive inotropic intervention: the phosphodiesterase inhibitors. 203 20

Controversy still exists concerning the therapy for viral myocarditis which manifests a wide variety of clinical symptoms. Vesnarinone, a quinolinone derivative that was developed as a positive inotropic agent with complex actions, including phosphodiesterase inhibition and cation channel modification, has recently been confirmed to improve the prognosis of patients with chronic heart failure. However, the precise mechanism of this beneficial effect is not yet clearly understood. In this study, using a murine model of acute viral myocarditis resulting from encephalomyocarditis virus infection, survival and myocardial damage were markedly improved by treatment with vesnarinone. In contrast, survival was not improved by treatment with amrinone, a phosphodiesterase inhibitor. Although vesnarinone did not inhibit viral replication or protect myocytes from viral direct cell injury, it did inhibit the increase in natural killer cell activity after viral infection. On the other hand, amrinone failed to inhibit natural killer cell activity. Both vesnarinone and amrinone suppressed the production of tumor necrosis factor-alpha. Therefore, we postulate that vesnarinone exerted its beneficial effects through an inhibition of natural killer cell activity, and that it serves as an immunomodulator providing new therapeutic possibilities for the treatment of viral myocarditis and/or immunological disorders.
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PMID:Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. Suppression of natural killer cell activity and tumor necrosis factor-alpha production. 808 62

Cytokines are soluble peptides that mediate cell-to-cell interactions via specific cell surface receptors. There is a growing body of evidence that cytokines may play an important role in the pathogenesis of heart failure, and the intriguing possibility has been postulated that anticytokine therapy may favorably alter the clinical outcome of heart failure. As cytokines are essentially pleiotropic and redundant in nature, elimination of a single cytokine from the biologic system often fails to have major consequences. Therefore, the prospect has been raised for developing immunomodulating therapy for heart failure, enabling the simultaneous modification of the actions of multiple cytokines. The recently observed clinical benefit of vesnarinone on mortality and morbidity in patients with heart failure has been attributed to this immunomodulation. In the murine model of myocarditis and heart failure, vesnarinone enhanced the cumulative survival rate without affecting virus replication on virus-induced cytopathic effects. Vesnarinone inhibited excessive cytotoxicity of natural killer cells presumably by suppressing activation mediated by K channel inhibition. Vesnarinone also inhibited the production of cytokines. Cytokine inhibitory effects were different from those of other phosphodiesterase inhibitors or direct elevation of intracellular cyclic adenosine monophosphate, suggesting that the effects did not appear to be derived solely from a cyclic adenosine monophosphate-elevating action. Such cytokine regulation also appeared to be different in normal patients and in patients with heart failure. In conclusion, vesnarinone exerts an immunomodulating effect by suppressing natural killer cell activity and inhibiting cytokine production. These findings may hold open the hope that immunomodulation could be a new therapeutic modality. However, further studies on the long-term safety and efficacy of vesnarinone are warranted to establish the eventual status of this agent in the treatment of heart failure.
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PMID:Vesnarinone: a potential cytokine inhibitor. 889 63

Management of acute viral myocarditis is still controversial. Amrinone, a noncatecholamine nonglycoside bipyridine agent, produces sustained improvement of cardiac function and symptomatology in congestive heart failure (CHF). Amrinone demonstrates phosphodiesterase inhibitory activity that is relatively selective for the major phosphodiesterase isozyme in cardiac muscles, PDE III, which specifically hydrolyzes cyclic 3'5' adenosine monophosphate (cAMP). We investigated the effects of amrinone in an animal model of acute CHF related to myocarditis caused by the encephalomyocarditis virus (EMCV). Female C3H mice were inoculated intraperitoneally (i.p.) with 500 plaque-forming units of EMCV in 0.1 ml of saline. A total of 96 mice were randomly assigned to four groups. Each animal was administered 0.2 ml of phosphate-buffered saline (PBS) containing amrinone at a concentration of 1, 10, or 50 mg/kg, or PBS as an infected control, injected i.p. once daily for 21 days, starting on day 1 after viral inoculation. Each group contains 20 to 30 mice. Infected untreated mice survived at 80% (n = 16), however, only 13% (n = 16) of mice treated with amrinone (50 mg/kg) survived (p < 0.01). Downregulation of cardiac cAMP occurred 1 day after the viral infection. Although amrinone (10 and 50 mg/kg) treatment significantly (p < 0.05) increased the cardiac cAMP content and the dose of 10 mg/kg could potentially retard death from CHF due to viral myocarditis. The higher (50 mg/kg) doses of amrinone may produce unfavorable effects when used to treat mammals with viral myocarditis and CHF.
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PMID:Effect of amrinone on murine viral myocarditis. 905 49

Cardiac failure is a syndrome which comprises ventricular dysfunction (confirmed by echocardiography) and compensating mechanisms (immediate activation of the sympathetic nerve and functioning of Starling's mechanism, within hours or days activation of RAAS within days or weeks hypertrophy of the heart). Cardiac failure develops rapidly either in a previously healthy subject (first extensive IM, diffuse myocarditis, acute aortic or mitral regurgitation) or in a damaged heart (IHD, KMP, defect) as a result of sudden excessive burdening (ischaemia, arrythmia, infection, surgery etc.) or spontaneously (end-stage). It is manifested above all by "backward" failure (pulmonary oedema). The pulmonary pressure must be rapidly reduced: i.v. nitrovasodilators act immediately, i.v. furosemide acts within 10-15 min. (in can, however, reduce the circulating volume which has not increased during the first failure). Also O2, anodynes. In the subacute stage (without any precise time limits) which may develop in serious cases from acute failure, or develop as a result of deterioration of chronic failure, in addition to congestion, symptoms caused by "forward" failure are in the foreground. These are symptoms caused by a reduced minute output and hyperfusion of tissue. It is indicated to administer substances which improve work tolerance, i.e. positive inotropics (digitalis, beta-agonist or phosphodiesterase inhibitors). If the blood pressure drops, a combination of dopamine and dobutamine should be administered; if the respiratory volume drops, artificial pulmonary ventilation, in case of persisting oedema continuous arteriovenous haemofiltration, in severe failure intraaorrtic balloon contrapulsation etc. In an irreversible state urgent or elective orthoptic transplantation of the heart should be considered. In chronic heart failure an important component of comprehensive treatment is in addition to treatment of congestion and hypoperfusion, prevention of "cardiovascular remodelling" by means of angiotensin convertase inhibitors etc. Which improve the quality of life and survival. Arrhythmias are an independent prognostic factor.
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PMID:[Acute and chronic heart failure]. 924 65

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival. Amrinone, pimobendan and vesnarinone, phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits, inhibited TNF-alpha production. Differential modulation of the production of IL-1beta and IL-6 was observed; amrinone and pimobendan enhanced the production of IL-1beta, whereas vesnarinone did not. As inotropic agents differentially modulate cytokine production, these agents may interfere with induction of inducible nitric oxide (NO) synthase through an inhibition of cytokine formation. Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure, further study is necessary to reach this conclusion. We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro. The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.
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PMID:The use of cytokine inhibitors. A new therapeutic insight into heart failure. 946 76

Congestive heart failure may be produced by a variety of disorders, including dilated cardiomyopathy, hypertension, and ischemic heart disease. We have developed experimental models of these diseases, and found gene expressions of proinflammatory cytokines increased in the hearts of these animals. Various drugs for heart failure modulate the production of cytokines in experimental models of heart failure. Pimobendan, an inhibitor of phosphodiesterase III prolonged survival, attenuated inflammatory lesions, and decreased the production of cytokines and nitric oxide. Recent studies have shown that these inhibitory effects are due to inhibition of activation of NF-kappaB. In contrast, digitalis increased the production of cytokines and exacerbated myocarditis. Interleukin-10 prolonged survival, attenuated myocardial injury, and appears promising as a treatment of heart failure due to viral myocarditis. Endothelin-1 plays an important pathophysiological role in heart failure, and treatment with an endothelin antagonist had a cardioprotective effect in experimental models of heart failure.
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PMID:The role of inflammatory mediators in the failing heart: immunomodulation of cytokines in experimental models of heart failure. 1130 31

Although a recent clinical study reported the beneficial effects of pentoxifylline (PTX), a phosphodiesterase inhibitor, on both symptoms and cardiac function in dilated cardiomyopathy (DCM), the precise mechanism of the drug has not been delineated. This study examined the efficacy of PTX in the treatment of experimental autoimmune myocarditis (EAM), as a model of the autoimmune mechanism involved in DCM. Oral PTX, or saline as control, was administered to Lewis rats at 150mg/kg body weight per day bid daily from 5 days before immunization with cardiac myosin until death on Day 21. Histological examination of the hearts showed PTX significantly reduced the severity of EAM. mRNA expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-6, and IL-10 was significantly reduced in peripheral blood mononuclear cells, but expression of IL-4 and IL-6 was upregulated in heart tissue. PTX in vitro could suppress T cell proliferation and inhibit TNF-alpha and interferon-gamma production. In conclusion, the immunomodulatory effects of PTX had a significant therapeutic result in EAM. This is the first report to describe such an effect of PTX in a specific animal model for DCM.
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PMID:Immunomodulatory effect of pentoxifylline in suppressing experimental autoimmune myocarditis. 1203 Mar 48

In the present review striking data showing that intensive care unit patients with acute heart failure and high-risk surgical patients may markedly benefit from the use of levosimendan are presented. Indeed, levosimendan is an effective new agent that acts via two complementary mechanisms. It enhances cardiac contractility by improving the response of the myofilaments to intracellular calcium, and it reduces the cardiac workload by opening the adenosine triphosphate-dependent potassium channels for the dilation of blood vessels. Because the therapeutic levels of levosimendan do not increase the intracellular calcium concentrations, levosimendan is less likely than traditional inotropes (beta-agonist inotropes or phosphodiesterase inhibitors) to elicit arrhythmias or impair diastolic relaxation. In fact, the results of recent clinical studies indicate that levosimendan offers significant hemodynamic and survival benefits when given to patients who are hospitalized for acute heart failure. Indeed, in the near future, it is likely that levosimendan may also prove effective for the treatment of patients with diastolic heart failure or for those with a low cardiac output following coronary artery bypass grafting. In addition, levosimendan has the potential of supporting the cardiac function during the initiation of beta-blocker therapy, for weaning patients from cardiopulmonary bypass, for individuals with valvular abnormalities and for those with myocarditis. Preliminary results also suggest that levosimendan may be beneficial for the treatment of patients with right ventricular heart failure. Although the use of levosimendan has been fully validated for the most common causes of acute heart failure, additional clinical trials are needed to safety broaden its therapeutic indications.
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PMID:The clinical experience with levosimendan in anesthesiology and in the intensive care unit. 1463 72

A previously described mammalian cell activity, called VPg unlinkase, specifically cleaves a unique protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection. For over three decades, the identity of this cellular activity and its normal role in the uninfected cell had remained elusive. Here we report the purification and identification of VPg unlinkase as the DNA repair enzyme, 5'-tyrosyl-DNA phosphodiesterase-2 (TDP2). Our data show that VPg unlinkase activity in different mammalian cell lines correlates with their differential expression of TDP2. Furthermore, we show that recombinant TDP2 can cleave the protein-RNA linkage generated by different picornaviruses without impairing the integrity of viral RNA. Our results reveal a unique RNA repair-like function for TDP2 and suggest an unusual role in host-pathogen interactions for this cellular enzyme. On the basis of the identification of TDP2 as a potential antiviral target, our findings may lead to the development of universal therapeutics to treat the millions of individuals afflicted annually with diseases caused by picornaviruses, including myocarditis, aseptic meningitis, encephalitis, hepatitis, and the common cold.
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PMID:An RNA virus hijacks an incognito function of a DNA repair enzyme. 2290 87


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