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Phosphodiesterase Inhibitor

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6681. Effect of cilostazol, a phosphodiesterase inhibitor, on carotid IMT in Japanese type 2 diabetic patients. (Abstract)

Effect of cilostazol, a phosphodiesterase inhibitor, on carotid IMT in Japanese type 2 diabetic patients. The aim of this study was to investigate the effect of cilostazol, a cAMP phosphodiesterase inhibitor, on carotid artery intima-media thickness (IMT) and on the incidence of cardiovascular events in Japanese subjects with type 2 diabetes. A total of 62 type 2 diabetic subjects were allocated equally to the cilostazol treatment group (n = 31) and the control group (n = 31). Carotid IMT

2004 Endocrine journal Controlled trial quality: uncertain

6682. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Full Text available with Trip Pro

The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Vardenafil, a novel selective phosphodiesterase type 5 inhibitor, was evaluated in its first large-scale at-home trial. A total of 601 men with mild to severe erectile dysfunction (ED) were enrolled in this multi-centre, randomized, double-blind, placebo-controlled trial of 12 weeks of treatment with either placebo or 5

2001 International journal of impotence research Controlled trial quality: predicted high

6683. The prophylactic use of the beta-blocker esmolol in combination with phosphodiesterase III inhibitor enoximone in elderly cardiac surgery patients. (Abstract)

The prophylactic use of the beta-blocker esmolol in combination with phosphodiesterase III inhibitor enoximone in elderly cardiac surgery patients. We assessed the influence of the prophylactic use of a combination of the IV beta-adrenergic blocker, esmolol, and the phosphodiesterase III inhibitor, enoximone, on postbypass hemodynamic status, inflammation, and endothelial and organ function in a prospective, randomized, placebo-controlled study in 42 patients aged >65 yr undergoing

2004 Anesthesia and analgesia Controlled trial quality: uncertain

6684. LPS-stimulated PMN activation and proinflammatory mediator synthesis is downregulated by phosphodiesterase inhibition: role of pentoxifylline. (Abstract)

burst. Phosphodiesterase inhibition decreases proinflammatory cytokine production and tissue injury after LPS challenge. Its effects on PMN function after LPS stimulation, however, have not been fully investigated. We hypothesized that LPS-induced TNF-alpha synthesis and subsequent PMN beta2-integrin expression and oxidative burst are downregulated by concomitant treatment with the non-specific phosphodiesterase inhibitor pentoxifylline (PTX).Whole blood was incubated with HBSS (control), LPS (100 (...) LPS-stimulated PMN activation and proinflammatory mediator synthesis is downregulated by phosphodiesterase inhibition: role of pentoxifylline. Excessive production of reactive oxygen species by PMN is associated with tissue damage during inflammation. LPS interacts with the cell surface receptor CD14, which generates transmembrane signals through Toll-like protein 4 leading to mitogen activated protein kinase (MAPK) p38 activation, cytokine synthesis, PMN beta2-integrin expression and oxidative

2004 Journal of Trauma

6685. Inhibition of phosphodiesterase type 5 by the activator of nitric oxide-sensitive guanylyl cyclase BAY 41-2272. Full Text available with Trip Pro

Inhibition of phosphodiesterase type 5 by the activator of nitric oxide-sensitive guanylyl cyclase BAY 41-2272. By the formation of cGMP, nitric oxide (NO)-sensitive guanylyl cyclase (GC) acts as the effector for the signaling molecule NO and mediates the relaxation of vascular smooth muscle and the inhibition of platelet aggregation. The compounds YC-1 and BAY 41-2272 are regarded as NO-independent activators and sensitizers of NO-sensitive GC. In vivo effects, for example, lowering blood (...) pressure and prolonging tail-bleeding times, turn the compounds into promising candidates for the therapy of cardiovascular diseases. However, YC-1 has also been shown to inhibit the major cGMP-degrading enzyme phosphodiesterase type 5 (PDE5). The synergistic properties of YC-1 on cGMP formation and degradation lead to an excessive NO-induced cGMP accumulation in cells, explaining the observed physiological effects. We assessed a potential inhibition of PDE5 by the new GC activator BAY 41-2272

2004 Circulation

6686. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. (Abstract)

Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia.Mice (...) homozygous for NPR-A (NPR-A+/+) and null mutants (NPR-A-/-) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate in NPR-A+/+ mice but not NPR-A-/- animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than did NPR-A+/+ mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg x kg(-1

2003 Circulation

6687. Effects of rolipram, a selective inhibitor of type 4 phosphodiesterase, on lipopolysaccharide-induced uveitis in rats. Full Text available with Trip Pro

Effects of rolipram, a selective inhibitor of type 4 phosphodiesterase, on lipopolysaccharide-induced uveitis in rats. To investigate effects of rolipram, an inhibitor of type 4 phosphodiesterase, on lipopolysaccharide (LPS)-induced uveitis in Wistar rats.A total of 100 microg LPS was injected into the rat footpad. Rolipram (Wako Pure Chemical, Osaka, Japan) was injected intraperitoneally 30 minutes before administration of LPS. Levels of intracameral protein, cells, E-selectin, tumor necrosis (...) factor (TNF)-alpha, interleukin (IL)-6, and nitrite were determined. E-selectin, TNF-alpha, IL-6, and inducible nitric oxide synthase (iNOS) mRNAs and immunohistochemical reactivity of nuclear factor (NF)-kappa B and TNF-alpha were also examined in the iris-ciliary body.After LPS injection, intracameral protein and cells increased from 18 to 30 hours later. Rolipram, however, inhibited elevation of protein and cells. After LPS injection, mRNA levels of E-selectin, TNF-alpha, and IL-6 in the iris

2004 Investigative Ophthalmology & Visual Science

6688. Effects of a phosphodiesterase-5 (PDE5) inhibitor on endothelium-dependent relaxation of myometrial small arteries. (Abstract)

Effects of a phosphodiesterase-5 (PDE5) inhibitor on endothelium-dependent relaxation of myometrial small arteries. In preeclampsia, endothelium-dependent function is markedly aberrant. Myometrial resistance arteries from women with preeclampsia show a minimal, wholly nitric oxide-mediated, bradykinin-induced relaxation. Our aim was to test that phosphodiesterase 5 (PDE5) inhibition could improve endothelium-dependent function in preeclampsia. Study design Small arteries dissected from (...) myometrial biopsies obtained at cesarean section from normal pregnant women (N=22) or women with preeclampsia (N=24) were mounted on wire or pressure myographs. Vessels were constricted (arginine vasopressin or U46619) and relaxed (bradykinin) before and after incubation with a PDE5 inhibitor, UK-343664.Endothelium-dependent vasodilatation was decreased in vessels from women with preeclampsia. 100 nmol/L UK-343664 did not affect normal pregnant but significantly improved relaxation of the vessels from

2004 American Journal of Obstetrics and Gynecology

6689. Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. (Abstract)

Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D (...) more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced

2003 Pulmonary Pharmacology & Therapeutics

6690. Phosphodiesterase type 4 inhibition of activated polymorphonuclear leukocytes in a simulated extracorporeal circulation model. Full Text available with Trip Pro

Phosphodiesterase type 4 inhibition of activated polymorphonuclear leukocytes in a simulated extracorporeal circulation model. Cardiopulmonary bypass is associated with a systemic inflammatory response syndrome and the risk of multiorgan injuries mediated by activated polymorphonuclear leukocytes. Phosphodiesterase type 4 is the predominant phosphodiesterase isozyme in polymorphonuclear leukocytes and plays a key role in the regulation of polymorphonuclear leukocyte activation. The aim (...) of this study was to examine the effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on the functional changes of polymorphonuclear leukocytes by using simulated extracorporeal circulation.Simulated extracorporeal circulation was established by recirculating heparinized human blood for 120 minutes on a membrane oxygenator with and without 10 micro mol/L rolipram. F-actin content and L-selectin and CD11b expression of polymorphonuclear leukocytes were measured by means of flow cytometry

2003 Journal of Thoracic and Cardiovascular Surgery

6691. Effects of a new phosphodiesterase enzyme type V inhibitor (UK 343-664) versus milrinone in a porcine model of acute pulmonary hypertension. (Abstract)

Effects of a new phosphodiesterase enzyme type V inhibitor (UK 343-664) versus milrinone in a porcine model of acute pulmonary hypertension. Perioperative pulmonary hypertension remains a clinical challenge. The phosphodiesterase enzyme type III inhibitor milrinone produces pulmonary vasodilation but lacks selectivity. Sildenafil, a phosphodiesterase enzyme type V inhibitor, can also induce relaxation of the pulmonary vasculature; however, only the oral formulation is presently available (...) , without appreciable changes in systemic arterial pressure or vascular resistance.Milrinone and UK 343-664 were equally effective as pulmonary vasodilators; however, only UK 343-664 exhibited a high degree of pulmonary selectivity. Potential uses for this new phosphodiesterase enzyme type V inhibitor warrant further study.

2004 Annals of Thoracic Surgery

6692. Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Full Text available with Trip Pro

Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Phosphodiesterase (PDE)-5 degrades guanosine 3',5'cyclic monophosphate (cGMP) and its inhibitor sildenafil citrate (Viagra) treats erectile dysfunction by smooth muscle relaxation through elevated cGMP. Sildenafil was examined in two guinea pig models of airways disease: guinea pigs exposed to LPS or sensitized guinea pigs with atopy exposed to ovalbumen. Ovalbumen exposure caused early- and late (...) microg/ml) caused AHR to histamine at 1 hour and macrophage, eosinophil, and neutrophil influx at 24 hours with raised NO. Sildenafil pretreatment inhibited LPS-induced AHR, leukocyte influx, and NO generation. The effectiveness of sildenafil was not dependent on endogenous NO because inhibition of NO synthase with Nomega-nitro-L-arginine methyl ester did not prevent its action. Inhibition of PDE5 by sildenafil was confirmed by elevated S-nitroso-N-acetylpenicillamine-induced cGMP generation

2004 American Journal of Respiratory and Critical Care Medicine

6693. Postnatal maturation of phosphodiesterase 5 (PDE5) in piglet pulmonary arteries: activity, expression, effects of PDE5 inhibitors, and role of the nitric oxide/cyclic GMP pathway. Full Text available with Trip Pro

Postnatal maturation of phosphodiesterase 5 (PDE5) in piglet pulmonary arteries: activity, expression, effects of PDE5 inhibitors, and role of the nitric oxide/cyclic GMP pathway. After birth and during the first days of extrauterine life, pulmonary arterial pressure is progressively reduced to reach the adult values. We hypothesized that changes in PDE5 activity might be involved in the pulmonary postnatal maturation of the nitric oxide (NO)/cGMP pathway. The PDE5 inhibitor sildenafil produced (...) vasorelaxant responses in isolated pulmonary arteries. These effects were similar in newborn (3-18 h) and 2-wk-old piglets, unchanged by endothelium removal, and markedly inhibited by the soluble guanylyl cyclase inhibitor ODQ. The peak of the transient vasorelaxant response to NO gas increased with postnatal age but was unaffected by PDE inhibition. However, the duration of the response to NO was significantly increased. The vasorelaxant response to sodium nitroprusside was potentiated by sildenafil

2004 Pediatric Research

6694. The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function. Full Text available with Trip Pro

The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function. Previous studies have demonstrated that antidepressants can enhance glucocorticoid receptor (GR) translocation and function, possibly through activation of cAMP and downstream cAMP dependent protein kinases. Accordingly, we examined GR function in cells treated with rolipram, a phosphodiesterase (PDE) type 4 inhibitor that antagonizes cAMP breakdown. Compared with vehicle-treated cells, rolipram alone (...) . These findings broaden the potential pathways by which PDE type 4 inhibitors can influence cellular function and indicate that these agents may have special utility in disorders associated with impaired GR-mediated feedback inhibition.

2002 Neuropsychopharmacology

6695. An interventional approach to block brain damage caused by Shiga toxin-producing Escherichia coli infection, by use of a combination of phosphodiesterase inhibitors. Full Text available with Trip Pro

An interventional approach to block brain damage caused by Shiga toxin-producing Escherichia coli infection, by use of a combination of phosphodiesterase inhibitors. We tested the combination of phosphodiesterase (PDE) 3 and PDE4 inhibitors as an interventional approach to prevent the development of brain damage after Shiga toxin (Stx)-producing Escherichia coli (STEC) infection, using mice with protein calorie malnutrition. The combination consisted of pentoxifylline and rolipram; the dose (...) of each inhibitor was 7.5 mg/kg. Treatment with this combination, which was administered intraperitoneally twice daily at 12-h intervals, increased serum concentrations of each inhibitor to >2 microg/mL and afforded significant levels of protection when it was continued for 3 days, starting on day 2 (95% survival rate; P<.001) or day 3 (63% survival rate; P<.01) of infection. The treatment reduced plasma levels of Stx2; consequently, immunoreactions of Stx2 were not found in the brain, and survivors

2004 Journal of Infectious Diseases

6696. Phosphodiesterase-3 inhibition prevents the increase in pulmonary vascular resistance following inhaled nitric oxide withdrawal in lambs. (Abstract)

Phosphodiesterase-3 inhibition prevents the increase in pulmonary vascular resistance following inhaled nitric oxide withdrawal in lambs. To determine the effects of inhaled nitric oxide on endogenous cyclic adenosine monophosphate in the intact lamb, and to determine the potential role of cyclic adenosine monophosphate in the rebound pulmonary hypertension associated with nitric oxide withdrawal.Prospective, placebo-controlled experimental study.University-based basic science research (...) laboratory.One-month-old lambs.Six 1-month-old control lambs, and 6 milrinone- (phosphodiesterase-3 inhibitor) treated lambs, were mechanically ventilated. Inhaled nitric oxide (40 ppm) was administered for 24 hrs and then acutely withdrawn. Sequential peripheral lung biopsies were obtained before, during, and 2 hrs after withdrawing inhaled nitric oxide therapy.In control lambs, initiation of nitric oxide decreased left pulmonary vascular resistance by 29.6%, and withdrawal rapidly increased pulmonary

2004 Pediatric Critical Care Medicine

6697. Prostaglandin E2-mediated anabolic effect of a novel inhibitor of phosphodiesterase 4, XT-611, in the in vitro bone marrow culture. Full Text available with Trip Pro

Prostaglandin E2-mediated anabolic effect of a novel inhibitor of phosphodiesterase 4, XT-611, in the in vitro bone marrow culture. The mechanism of osteoblast formation by a novel PDE4 inhibitor, XT-611, was studied in the in vitro bone marrow culture system. The compound potentiated the osteoblast differentiation through accumulation of cyclic AMP after autocrine stimulation of EP4 receptor by PGE2 in pro-osteoblastic cells.We previously reported that inhibitors of phosphodiesterase (PDE)4 (...) isoenzyme increase osteoblast formation in an in vitro bone marrow culture system and inhibit bone loss in animal osteoporosis models. Here we investigated the mechanism of the effect of a novel PDE4 inhibitor, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]-purin-5-one (XT-611), on osteoblast formation in the in vitro bone marrow culture system.Rodent bone marrow cells were cultured in the presence of 0.2 mM ascorbic acid phosphate ester, 1 mM beta-glycerophosphate, and 10 nM dexamethasone for 10

2003 Journal of Bone and Mineral Research

6698. Phosphodiesterase 4 inhibition synergizes with relaxin signaling to promote decidualization of human endometrial stromal cells. Full Text available with Trip Pro

-elevating agents in vitro. Our previous findings indicated that the cAMP-degrading activities of phosphodiesterases (PDE) and signaling of the peptide hormone relaxin are coupled in human endometrial stromal cells. In the present study we have chosen a pharmacological approach to test whether relaxin binding and PDE inhibition cooperate to induce decidualization. Measurement of PDE activity and relaxin-stimulated cAMP accumulation in the presence of diverse PDE inhibitors identified PDE4 and PDE8 (...) Phosphodiesterase 4 inhibition synergizes with relaxin signaling to promote decidualization of human endometrial stromal cells. The decidualization of endometrial stromal cells in the secretory phase of the menstrual cycle is an essential prerequisite for the implantation of a blastocyst. This profound differentiation process is accompanied by sustained elevated intracellular cAMP concentrations in vivo. Primary cell cultures of endometrial stromal cells decidualize by treatment with cAMP

2004 Journal of Clinical Endocrinology and Metabolism

6699. Cilostazol, an inhibitor of type 3 phosphodiesterase, stimulates large-conductance, calcium-activated potassium channels in pituitary GH3 cells and pheochromocytoma PC12 cells. Full Text available with Trip Pro

Cilostazol, an inhibitor of type 3 phosphodiesterase, stimulates large-conductance, calcium-activated potassium channels in pituitary GH3 cells and pheochromocytoma PC12 cells. The effects of cilostazol, a dual inhibitor of type 3 phosphodiesterase and adenosine uptake, on ion currents were investigated in pituitary GH(3) cells and pheochromocytoma PC12 cells. In whole-cell configuration, cilostazol (10 microm) reversibly increased the amplitude of Ca(2+)-activated K(+) current [I(K(Ca (...) and a decrease in mean closed time. Under current-clamp configuration, cilostazol decreased the firing frequency of action potentials. In pheochromocytoma PC12 cells, cilostazol (10 microM) also increased BK(Ca) channel activity. Cilostazol-mediated stimulation of I(K(Ca)) appeared to be not linked to its inhibition of adenosine uptake or phosphodiesterase. The channel-stimulating properties of cilostazol may, at least in part, contribute to the underlying mechanisms by which it affects neuroendocrine

2004 Endocrinology

6700. Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension. Full Text available with Trip Pro

Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension. Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration (...) phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.

2004 Circulation Research

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