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)

G619, a 4-OH-isophthalic acid derivative, was studied for its capacity to inhibit platelet aggregation. G619 dose-dependently inhibited U46619, collagen, ADP, PAF, thrombin and epinephrine-induced platelet aggregation in vitro. The IC50 values for inhibition of U46619-induced human and rabbit platelet aggregation were 39 and 43 microM, respectively. G619, at 100 microM, inhibited high concentration collagen (10 micrograms/ml)-induced aggregation of rabbit platelets pretreated with indomethacin and increased the level of cAMP in washed rabbit platelets by 30% (p less than 0.01 vs basal). However, G619, did not inhibit fibrinogen binding to GPIIb/IIIa receptor, phosphodiesterase, U46619-induced contractile responses on canine saphenous vein or rabbit aorta, calcium-induced vasoconstriction and thrombin or PAF-induced elevation of [Ca++]i in platelets in vitro. In vivo, the U46619-induced maximal thrombocytopenia in rats was reduced from 40% (vehicle) to 22% and 18% by 10 and 30 mg/kg of G619 i.v., respectively. G619 (30 mg/kg) had no effect on the U46619-induced vasopressor response or sudden death in rats, and had no effect on TxB2 formation. Our results indicate that G619 is a broad-spectrum platelet aggregation inhibitor and may have its effect on a common mechanism for platelet aggregation besides an effect on the thromboxane A2 receptor.
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PMID:Pharmacological profile of G619, a new platelet aggregation inhibitor. 141

Pulmonary hypertension, systemic vasodilation and the supply dependency of oxygen uptake are the major problems associated with sepsis. Thus, the goal of haemodynamic therapy in septic patients is an increase in cardiac output large enough to permit adequate tissue oxygenation. The purpose of this study was to establish whether the additional use of the phosphodiesterase inhibitor amrinone is useful in hypodynamic septic patients with inadequate tissue perfusion. Nine patients who had developed the clinical signs of sepsis (temperature greater than 38.5 degrees C, leukocytosis greater than 15,000/mm3, thrombopenia less than 100,000/mm3 or a drop in platelet count greater than 30%, cardiovascular shock) were given amrinone 30 micrograms.kg-1.min-1 for one hour. All patients showed mixed venous oxygen saturations below 70% and oxygen extraction rates above 30%, despite maximum catecholamine therapy. Haemodynamic parameters were measured with the help of a pulmonary artery catheter. Statistical significance was checked using the Wilcoxon signed-ranks test. During amrinone application cardiac index increased significantly from 4.6.1.81.min-1.m-2 to 5.6 +/- 1.81.min-1.m-2 (p less than 0.01), while central venous pressure was kept constant by volume supply. Mean pulmonary artery pressure remained nearly unchanged, whereas mean arterial pressure dropped significantly from 91 +/- 13 mmHg to 75 +/- 8 mmHg (p less than 0.01). The oxygen supply rose during administration of amrinone by an average of 17%, which led to a rise in oxygen uptake. Independence of oxygen uptake from oxygen supply, however, could not be attained. In septic patients, amrinone increases cardiac output via pulmonary vasodilation. However, pronounced systemic vasodilation lowers arterial blood pressure, enhancing the risk of myocardial ischaemia.
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PMID:[Amrinone for cardiovascular therapy in hypodynamic septic patients?]. 161 30

Amrinone is a selective inhibitor of phosphodiesterase fraction 3 in both cardiac and smooth muscle. Intravenous administration in humans produces increased contractility and vasodilation of venous capacitance and arterial conductance vessels. The elimination half-life in healthy patients is reported to be 2.6 to 4.1 hours, making it the only long-acting positive inotropic agent available that can be administered either as an intravenous bolus or by infusion. A low incidence of side effects, often minor, has been reported with intravenous use. Thrombocytopenia does not seem to be a problem with short-term use. Amrinone represents a new approach in the pharmacologic therapy for ventricular dysfunction following cardiac surgery.
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PMID:Amrinone: pharmacokinetics and pharmacodynamics. 252 Oct 45

The bipyridine derivative amrinone is a specific phosphodiesterase III blocking agent. In vitro and in vivo studies show a dose-dependent increase in myocardial contractility induced by amrinone. In patients with congestive heart failure, the inotropic and vasodilator effects of amrinone contribute to cardiac improvement. When amrinone is used, the increase in myocardial oxygen consumption due to increased contractility is offset by the reductions in preload and afterload. In hearts with very high wall tension, myocardial oxygen consumption may even decrease with amrinone. Amrinone therapy is not accompanied by significant increases in heart rate. Tachyphylaxis has not been observed. The elimination half-life ranges between 2.5 and 3.5 h. A large quantity of amrinone is excreted unchanged, and therefore in cases of renal impairment the possibility of cumulation exists. The main adverse reaction of amrinone is a reversible thrombocytopenia induced by a dose-dependent decrease in platelet survival time. Therefore, frequent platelet counts are necessary when amrinone is administered. Numerous studies in patients with chronic congestive heart failure confirmed the beneficial hemodynamic effects of amrinone. Experience in the treatment of acute perioperative heart failure with amrinone are still limited, but the present results are encouraging; an additive effect of amrinone to catecholamines seems especially promising in the therapy of severe postoperative low-cardia-output syndrome.
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PMID:[Amrinone (Wincoram)--a new positive inotropic and vasodilator agent]. 304 13

This study was designed to determine the in vivo effects of a phosphodiesterase inhibitor (HL 725) in combination with a thromboxane synthase inhibitor (CGS 13080) or prostacyclin (PGI2) as inhibitors of thrombin-induced changes in platelet function and prevention of sudden death. In anesthetized rabbits, the i.v. administration of thrombin reduced the circulating number of platelets from 256,000 +/- 32,000/microliter to 8 +/- 2% of the initial value, and produced a right ventricular thrombus of 285 +/- 52 mg. All animals died within 5 min. PGI2 (0.3 microgram/kg/min) or HL 725 (2 micrograms/kg/min) did not prevent the thrombin-induced fall in the number of circulating platelets, the formation of a right ventricular thrombus or death. Administration of 2 mg/kg of CGS 13080 reduced significantly the mass of the right ventricular thrombus, but did not prevent completely the reduction in the circulating platelet count or death. After the administration of the combination of CGS 13080 with HL 725, the thrombocytopenia was transient, the right ventricular thrombus was reduced (P less than .05), and survival increased to 75% (P less than .05). The combination of PGI2 with HL 725 was similar in benefit to the combination of CGS 13080 and HL 725. Survival for the group of the combination of CGS 13080 with 725 was significantly greater than survival in the CGS 13080 or HL 725 groups, indicating a synergistic effect for the combination. The decrease in blood pressure response to HL 725 was greater with PGI2, but not with CGS 13080.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the effects of a thromboxane synthase inhibitor or prostacyclin in combination with a phosphodiesterase inhibitor for prevention of experimental thrombosis and sudden death in rabbits. 329 21

Clinical trials with new inotropic, non-adrenergic agents with vasodilating properties have open new perspectives for the treatment of acute and chronic heart failure. If their mechanism of action is not exactly known, they are likely to increase C.AMP by phosphodiesterase inhibition. A clear distinction has to be made concerning short- and long-term administration of these drugs. Amrinone (A) has been administered to 10 patients with low postoperative cardiac output as unique inotropic therapy and to 34 patients in severe cardiogenic shock, despite optimal treatment. In the latter group, A was added to the preliminary drugs. In both groups of patients, hemodynamics improved significantly, except in 4 patients in group II, who died. Except in one case with thrombocytopenia and one with supraventricular dysrhythmias, no serious side-effects were noted. No long-term treatment has been carried out in our institution. The literature has widely reported that the new inotropic drugs used in class III and IV patients, are likely to increase patient's well-being and exercise capacity, but not life expectancy.
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PMID:New inotropic-vasodilating drugs in acute and chronic heart failure. 376 91

gamma-Oxo(1,1'-biphenyl)-4-butanoic acid (fenbufen) and biphenylacetic acid have effects on platelets similar to other non-steroidal antiinflammatory agents. In vitro biphenylacetic acid (BPAA), a metabolite of fenbufen, is more potent than fenbufen and in vivo metabolism of fenbufen to BPAA is probably required for activity. The arachidonate-thromboxane system appears to play a critical role in explaining a major part of the mechanism of action of these agents on platelets and other systems. Fenbufen, however, also inhibits collagen-induced platelet aggregation without requiring metabolic conversion to BPAA. The mechanism for this inhibition appears to be independent of the arachidonate-thromboxane system, as well as unrelated to serotonin release or inhibition of phosphodiesterase activity. The effects of fenbufen and BPAA on platelet biochemistry and function suggest their utility as clinical anti-thrombotic agents. This is further supported by the absence of any thrombocytopenia or bleeding tendency in animals and man.
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PMID:A review of the effects of fenbufen and a metabolite, biphenylacetic acid, on platelet biochemistry and function. 625 45

Anagrelide is a quinazoline compound developed as a potent inhibitor of platelet aggregation. During studies in human it has produced rapid and selective thrombocytopenia and has therefore been evaluated for use in conditions associated with thrombocythaemia. Anagrelide significantly inhibits human megakaryocyte colony development in vitro by preventing full megakaryocyte maturation, and inhibits platelet aggregation as a result of potent inhibition of cyclic adenosine monophosphate (cAMP) phosphodiesterase activity. In 60 to 93% of patients with essential or myeloproliferative thrombocythaemia anagrelide produces sustain reductions in platelet counts and also reduces the incidence of disease-related symptoms. Most adverse effects are related to its vasodilatory or positive inotropic properties. This new agent appears promising in the treatment of thrombocytosis in patients with chronic myeloproliferative diseases, especially in younger persons in whom the risk of leukaemogenic transformation with some alternative drugs is of particular concern.
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PMID:[Anagrelide--new antiplatelet drug]. 784 31

The following study was performed to determine the effects of phosphodiesterase IV (PDE-IV) inhibition and its attenuation of tumor necrosis factor (TNF alpha) production in a rat model of the Adult Respiratory Distress Syndrome (ARDS). Rats were either unexposed (n = 8), pretreated orally with vehicle prior to intratracheal saline exposure (n = 11), pretreated with vehicle prior to 7 mg/kg intratracheal endotoxin (LPS) administration (n = 22), or pretreated with 5 or 50 mg/kg rolipram prior to LPS exposure (n = 6 and 7, respectively). Blood was sampled 1 and 3 hr post LPS exposure and assayed for plasma TNF alpha concentrations. Twenty-four hours after LPS exposure, blood was sampled again for hematologic measurements. The rats were then anesthetized and exsanguinated. Bronchoalveolar lavage (BAL) was performed after the lung of each rat was removed and weighed. Rolipram pretreatment was protective against LPS-induced mortality and also resulted in reduced plasma TNF alpha concentrations. LPS induced pulmonary edema, as indicated by wet/dry lung weight ratio (W/D) and total BAL protein content (TP) was attenuated by rolipram pretreatment. LPS-induced alveolar hemorrhage was reduced by rolipram pretreatment, but LPS-induced pulmonary neutrophilia was not. The hemoconcentration induced by LPS was reduced by rolipram, as was the LPS-induced thrombocytopenia. However, LPS-induced changes in circulating leukocyte populations were actually exacerbated by rolipram. LPS-induced alterations in renal and hepatic function, indicated by increased blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were inhibited by rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic intervention in a rat model of ARDS: IV. Phosphodiesterase IV inhibition. 838 94

Lethal circulatory shock during microbial sepsis is thought to be initiated by early molecular events, including production of tumor necrosis factor (TNF) and cytokine-mediated upregulation of neutrophil (PMN) function, irrespective of the causative organism. The phosphodiesterase inhibitor pentoxifylline (PTX) inhibits TNF gene transcription and modulates PMN function, and has been shown to improve outcome in experimental sepsis. We hypothesized that PTX would attenuate gram-negative and fungal septic shock by different mechanisms: reduced TNF production in Escherichia coli (EC) sepsis vs. enhanced PMN-mediated defense during Candida albicans (CA) fungemia. Conscious chronically catheterized rats received PTX (25 mg/kg, i.v.) before i.v. challenge with 10(10) viable EC (serotype 055:B5), 10(9) viable serotype A yeast-phase CA (each the LD100 in < 24 hr in naive rats), or normal sterile saline (NSS), and then PTX posttreatment (6.5 mg/hr x 4.5 hr). Treatment controls received NSS before and after challenge. Serum TNF peaked 1.5 hr after EC infection in NSS-treated animals (1654 +/- 390 U/ml, mean +/- SE), and was significantly reduced by PTX (120 +/- 32 U/ml, P < 0.01), but PTX did not improve 24 hr survival. PTX also aggravated systemic hypotension after EC, and did not modify neutropenia, thrombocytopenia, or microvascular permeability assessed by organ wet/dry weight (W/D) ratios. Peak serum TNF in CA + NSS animals (130 +/- 45 U/ml) was delayed 8 hr compared to EC animals, and were not reduced by PTX (67 +/- 25 U/ml, P = NS). Moreover, PTX did not alter CA-induced mortality, hypothermia, hypotension, neutropenia, increased lung W/D, or interstitial and alveolar hemorrhage. We conclude that PTX-induced suppression of endogenous TNF production does not prevent gram-negative shock in this model, possibly due to impaired TNF-mediated antibacterial host defense. Since fungal septic shock with acute disseminated candidiasis evolves prior to significant increases in circulating TNF, PTX also appears ineffective in its treatment.
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PMID:Effects of pentoxifylline on tumor necrosis factor production and survival during lethal E. coli sepsis vs. disseminated candidiasis with fungal septic shock. 848 22


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