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Phosphodiesterase Inhibitor

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6541. The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-alpha production in whole blood from COPD patients. (Abstract)

The novel phosphodiesterase 4 inhibitor, CI-1044, inhibits LPS-induced TNF-alpha production in whole blood from COPD patients. Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious (...) in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-alpha release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF

2005 Pulmonary Pharmacology & Therapeutics

6542. Phosphodiesterase type 4 inhibitor rolipram inhibits activation of monocytes during extracorporeal circulation. Full Text available with Trip Pro

Phosphodiesterase type 4 inhibitor rolipram inhibits activation of monocytes during extracorporeal circulation. Cardiopulmonary bypass is associated with systemic inflammatory response syndrome and risk of multiorgan injury mediated by activated leukocytes. Phosphodiesterase type 4 is the predominant phosphodiesterase isozyme in leukocytes and plays a key role in the regulation of leukocyte activation. The aim of this study was to examine the effect of rolipram, a selective phosphodiesterase (...) and the decrease in L-selectin expression of monocytes in response to simulated extracorporeal circulation. Rolipram inhibited the increase in C4d fragment and interleukin-6, but it did not affect the increase in Bb fragment or C5b-9.Rolipram inhibited changes in adhesion molecule expression and interleukin-6 release by activated monocytes in simulated extracorporeal circulation. This study suggests that phosphodiesterase type 4 inhibition could be feasible therapeutic strategy to prevent exaggerated

2005 Journal of Thoracic and Cardiovascular Surgery

6543. The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques. Full Text available with Trip Pro

The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques. The study was conducted to determine whether the phosphodiesterase (PDE) 3 inhibitor ORG 9935 prevents the resumption of meiosis in primate oocytes during natural menstrual cycles.Regularly cycling adult female macaques (n=8) were followed during the follicular phase and then started on a 2-day treatment regimen of human recombinant gonadotropins to control (...) the timing of ovulation. Monkeys received no further treatment (controls) or ORG 9935. Oocytes were recovered by laparoscopic follicle aspiration 27 h after an ovulatory stimulus, cultured in vitro in the absence of inhibitor and inseminated. The primary outcome was the meiotic stage of the oocyte.In six ORG 9935 cycles, five of the recovered oocytes were germinal vesicle (GV)-intact, and one exhibited GV breakdown (GVBD). In contrast, all three oocytes that recovered during control cycles were GVBD (p

2008 Contraception

6544. Combined use of phosphodiesterase-5 inhibitors and selective serotonin reuptake inhibitors for temporary ejaculation failure in couple undergoing assisted reproductive technologies. (Abstract)

Combined use of phosphodiesterase-5 inhibitors and selective serotonin reuptake inhibitors for temporary ejaculation failure in couple undergoing assisted reproductive technologies. To explore the drug treatment for temporary ejaculation failure in couple undergoing assisted reproductive technologies (ART).Case report.Andrology unit, center for reproductive medicine.Five patients suffering from temporary ejaculation failure during ART.Assisted reproductive technology. Semen samples were (...) collected by masturbation. The combined use of phosphodiesterase-5 inhibitor (PDE5-I; vardenafil, 10 mg) and selective serotonin reuptake inhibitor (SSRI; sertraline, 50 mg) to treat patients who failed to collect semen on the day of egg retrieval.Five patients with unexpected ejaculation failure during ART treatments were identified; two patients could not produce spermatozoa 3 h after taking PDE5-I (sildenafil, 50 mg), However, the use of PDE5-I (vardenafil, 10 mg) plus SSRI (sertraline, 50 mg

2008 Fertility and Sterility

6545. A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro. (Abstract)

A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro. Airway smooth muscle (ASM) cells may contribute to airway remodeling through the release of growth factors, cytokines, and extracellular matrix (ECM) proteins. The effect of current asthma therapies on this release is not known.We examined the effect of corticosteroids, long-acting beta(2)-agonists, and a phosphodiesterase 4 (PDE4) inhibitor on ASM-released connective tissue growth factor (CTGF), collagen I (...) , or fibronectin in either cell type, whereas corticosteroids alone induced the expression of CTGF, collagen I, and fibronectin. These drugs did not prevent the accumulation of TGF-beta-induced proteins in bronchial rings, whereas the PDE4 inhibitor roflumilast inhibited TGF-beta-induced CTGF, collagen I, and fibronectin.In our model, current asthma therapies are not able to inhibit matrix protein deposition from ASM cells. The results of this study suggest that the PDE4 inhibitor roflumilast may have a role

2006 Journal of Allergy and Clinical Immunology

6546. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Full Text available with Trip Pro

Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Sildenafil was recently approved for the treatment of pulmonary arterial hypertension. The beneficial effects of phosphodiesterase type 5 (PDE5) inhibitors in pulmonary arterial hypertension are thought to result from relatively selective vasodilatory and antiproliferative effects on the pulmonary vasculature and, on the basis of early (...) in the perfused heart (modified Langendorff preparation) and isolated cardiomyocytes, in RVH but not normal RV. PDE5 inhibition leads to increases in both cGMP and cAMP in RVH but not normal RV. Protein kinase G activity is suppressed in RVH, explaining why the PDE5 inhibitor-induced increase in cGMP does not lead to inhibition of contractility. Rather, it leads to inhibition of the cGMP-sensitive PDE3, explaining the increase in cAMP and contractility. This is further supported by our findings that, in RVH

2007 Circulation

6547. Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Full Text available with Trip Pro

Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Phosphodiesterase (PDE) inhibitors are important therapeutic agents, but their effects on photoreceptor PDE (PDE6) and photoreceptor cells are poorly understood. The potency and selectivity of various classes of PDE inhibitors on purified rod and cone PDE6 and on intact rod outer segments (ROS) were characterized.The inhibition constant (K(i)) of isozyme (...) -selective PDE inhibitors was determined for purified rod and cone PDE6. Perturbations of cGMP levels in isolated ROS suspensions by PDE inhibitors were quantitated by a cGMP enzyme-linked immunoassay.Most PDE5-selective inhibitors were excellent PDE6 inhibitors. Vardenafil, a potent PDE5 inhibitor (K(i) = 0.2 nM), was the most potent PDE6 inhibitor tested (K(i) = 0.7 nM). Zaprinast was the only drug that inhibited PDE6 more potently than did PDE5. PDE1-selective inhibitors were equally effective

2005 Investigative Ophthalmology & Visual Science

6548. The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor-α and leukotriene B4 in a novel human whole blood assay Full Text available with Trip Pro

The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor-α and leukotriene B4 in a novel human whole blood assay 1. The aim of this study was to assess the inhibitory activities of phosphodiesterase type 4 (PDE4) inhibitors on tumour necrosis factor-alpha (TNF-alpha) and leukotriene B4 (LTB4) production in a novel human whole blood assay. 2. Lipopolysaccharide (LPS) stimulation of human whole blood caused a time dependent increase in TNF-alpha and prostaglandin E2 (PGE2 (...) ) plasma levels. Inhibition of LPS-induced TNF-alpha by the selective PDE4 inhibitor RP73401 was proportionally enhanced with endogenous PGE2 (maximal after 24 h). In contrast, blocking endogenous PGE2 production with indomethacin in blood stimulated with LPS for 24 h decreased the potency of RP73401 to that observed with a 4 h LPS incubation. 3. Non-selective and selective PDE4 inhibitors showed greater inhibition of LPS-induced TNF-alpha after 24 h compared to 4 h. Stereoselectivity was only achieved

1999 British journal of pharmacology

6549. Reduced airway hyperresponsiveness by phosphodiesterase 3 and 4 inhibitors in guinea-pigs. Full Text available with Trip Pro

Reduced airway hyperresponsiveness by phosphodiesterase 3 and 4 inhibitors in guinea-pigs. The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48h after OA, a significant reduction (P<0.01) of the leftward shift of the dose-response (...) curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (P<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE

1999 Mediators of inflammation

6550. Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor Full Text available with Trip Pro

Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor 1. We have investigated the effects of RP 73401, a novel, potent and highly selective cyclic nucleotide phosphodiesterase (PDE) type IV inhibitor, in guinea-pig and rat models of bronchoconstriction and allergic inflammation. In some models, the effects of RP 73401 have been compared with those of the standard PDE type IV inhibitor, rolipram. 2. RP 73401 (0.4-400 micrograms kg (...) -1, intratracheally (i.t.) on lactose) inhibited antigen-induced bronchospasm in previously sensitized conscious guinea-pigs (ID50: 7 +/- 1 micrograms kg-1) and in anaesthetized rats (ID50: 100 +/- 25 micrograms kg-1). Rolipram inhibited the antigen-induced bronchospasm in guinea-pigs with an ID50 of 5 +/- 1 micrograms kg-1. In guinea-pig bronchoalveolar lavage (BAL) fluid, total inflammatory cell and eosinophil numbers were reduced by RP 73401 (ID50s: 3.9 +/- 0.8 micrograms kg-1 and 3.2 +/- 0.7

1994 British journal of pharmacology

6551. Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram. Full Text available with Trip Pro

Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP-specific phosphodiesterase: comparison with rolipram. 1. We have investigated the inhibitory potency of RP 73401, a novel, highly selective and potent inhibitor of cyclic AMP-specific phosphodiesterase (PDE IV), against partially-purified PDE isoenzymes from smooth muscle and the particulate PDE IV from guinea-pig eosinophils. The inhibitory effects of RP 73401 on the generation of superoxide (.O2 (...) -), major basic protein (MBP) and eosinophil cationic protein (ECP) from guinea-pig eosinophils have also been studied. 2. RP 73401 potently inhibited partially-purified cyclic AMP-specific phosphodiesterase (PDE IV) from pig aortic smooth muscle (IC50 = 1.2 nM); it was similarly potent against the particulate PDE IV from guinea-pig peritoneal eosinophils (IC50 = 0.7 nM). It displayed at least a 19000 fold selectivity for PDE IV compared to its potencies against other PDE isoenzymes. Rolipram

1995 British journal of pharmacology

6552. Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts Full Text available with Trip Pro

Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts 1. Cardiac fibroblasts play an important role in the pathophysiology of cardiac remodelling induced by hypertension and myocardial infarction by undergoing proliferation and depositing extracellular matrix proteins such as collagen. We have examined the effects of atrial natriuretic peptide (ANP) on proliferation and collagen synthesis by adult rat and human (...) cardiac fibroblasts in culture. 2. In cells from both species radioligand studies using 125I-ANP suggested that the majority of binding sites (> 85%) were non-guanylyl cyclase-linked (NPR-C subtype). Nonetheless ANP (10(-9) to 10(-6) M), in the presence of zaprinast, an inhibitor of phosphodiesterase 5 (PDE5), increased fibroblast cyclic GMP levels 3-5 fold in a concentration-dependent manner (P < 0.05). 3. ANP (10(-11) to 10(-6) M), a NPR-C ligand, C-ANF4-23 (10(-11) to 10(-6) M) and zaprinast alone

1998 British journal of pharmacology

6553. cGMP inhibition of heart phosphodiesterase: is it clinically relevant? Full Text available with Trip Pro

cGMP inhibition of heart phosphodiesterase: is it clinically relevant? 7860725 1995 03 20 2018 11 13 0021-9738 95 2 1995 Feb The Journal of clinical investigation J. Clin. Invest. cGMP inhibition of heart phosphodiesterase: is it clinically relevant? 445 Beavo J A JA eng Comment Editorial Review United States J Clin Invest 7802877 0021-9738 0 Phosphodiesterase Inhibitors 31C4KY9ESH Nitric Oxide EC 3.1.4.- Phosphoric Diester Hydrolases H2D2X058MU Cyclic GMP AIM IM J Clin Invest. 1995 Feb;95(2 (...) ):794-802 7860763 Animals Cyclic GMP pharmacology physiology Humans Myocardium enzymology Nitric Oxide physiology Phosphodiesterase Inhibitors pharmacology Phosphoric Diester Hydrolases metabolism 11 1995 2 1 1995 2 1 0 1 1995 2 1 0 0 ppublish 7860725 10.1172/JCI117683 PMC295485 Proc Natl Acad Sci U S A. 1970 Jun;66(2):398-403 5271171 N Engl J Med. 1991 Nov 21;325(21):1468-75 1944425 Adv Cyclic Nucleotide Protein Phosphorylation Res. 1984;17:249-58 6145321 Proc Natl Acad Sci U S A. 1991 Feb 15;88(4

1995 Journal of Clinical Investigation

6554. Differential effects of non-selective and selective phosphodiesterase inhibitors on human eosinophil functions. Full Text available with Trip Pro

Differential effects of non-selective and selective phosphodiesterase inhibitors on human eosinophil functions. 1. The effect of non-selective (3-isobutyl-1-methylxanthine, IBMX; theophylline) and type IV- or type III/IV-selective (rolipram, RP 73401; zardaverine, tolafentrine) phosphodiesterase (PDE) inhibitors on human eosinophil functions was investigated. 2. For this purpose human eosinophils were purified from blood of healthy donors by a magnetic cell separation (MACS) technique (...) secretion. Only the IC50 value of IBMX for inhibition of chemiluminescence was lowered by about one order of magnitude in the presence of salbutamol. 4. In contrast, none of the selective PDE inhibitors tested substantially inhibited the two cell responses at concentrations up to 10 mumol l-1. This was surprising because all of the compounds investigated inhibited PDE IV activity in the cell-free system with IC50 values which were at least 30 fold lower than the highest concentration of the compounds

1995 British journal of pharmacology

6555. Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. Full Text available with Trip Pro

Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-alpha production. Using compounds of two (...) distinct chemical structural classes, a quinazolinedione (CP-77059) and a 4 arylpyrrolidinone (rolipram), we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced TNF-alpha production in vitro in sodium periodate-elicited murine macrophages (IC50s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-alpha induced by a sublethal LPS injection; (ii) LPS-induced

1995 Clinical and experimental immunology

6556. Inhibition of Phosphodiesterase Type IV Suppresses Human Immunodeficiency Virus Type 1 Replication and Cytokine Production in Primary T Cells: Involvement of NF-κB and NFAT Full Text available with Trip Pro

Inhibition of Phosphodiesterase Type IV Suppresses Human Immunodeficiency Virus Type 1 Replication and Cytokine Production in Primary T Cells: Involvement of NF-κB and NFAT Rolipram, a phosphosdiesterase type IV-specific inhibitor, prevented p24 antigen release from anti-CD3-activated human immunodeficiency virus (HIV)-infected T cells and CD4(+)-cell depletion associated with viral replication in a dose-responsive manner but minimally inhibited T-cell proliferation. Moreover, rolipram reduced (...) and electrophoretic mobility shift assays. Exogenous addition of TNF-alpha in the presence of rolipram restored NF-kappaB but not NFAT activation or p24 release. Addition of dibutyryl-cyclic AMP (dBcAMP) mimicked the effects of rolipram on p24 antigen release, NF-kappaB activation, and TNF-alpha secretion, but it did not affect NFAT activation or IL-10 production. The protein kinase A inhibitor KT5720 prevented the inhibition of TNF-alpha secretion but not that of HIV type 1 (HIV-1) replication caused by rolipram

1998 Journal of virology

6557. Effects of RP 73401, a novel, potent and selective phosphodiesterase type 4 inhibitor, on contractility of human, isolated bronchial muscle. Full Text available with Trip Pro

Effects of RP 73401, a novel, potent and selective phosphodiesterase type 4 inhibitor, on contractility of human, isolated bronchial muscle. 1. The aim of this study was to investigate the smooth muscle relaxant effects of the novel, selective phosphodiesterase (PDE) type 4 inhibitor, RP 73401 in comparison with the classical PDE 4 inhibitor, rolipram, the non-selective PDE inhibitor, theophylline and the beta-adrenoceptor agonist, isoprenaline on the human, isolated bronchus. 2. At resting (...) tone, the rank order of potency (pD2) for the relaxants was RP 73401 > or = rolipram > or = isoprenaline > theophylline. In terms of maximum relaxation produced (Emax) the PDE 4-selective inhibitors were similar, but the maximal effects (70-75% of theophylline, 3 mM) were lower than that observed with isoprenaline (98% of theophylline, 3 mM) or theophylline itself (100%). 3. On the human isolated bronchus pre-contracted with acetylcholine (ACh, 0.1 or 1.0 mM), the rank order of potency remained

1996 British journal of pharmacology

6558. Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits. Full Text available with Trip Pro

Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits. 1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated

1996 British journal of pharmacology

6559. Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: in vitro and in vivo characterization. Full Text available with Trip Pro

Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: in vitro and in vivo characterization. 1. The aim of this study was to investigate the cardiovascular effects of a novel, potent and specific phosphodiesterase 5 (PDE 5) inhibitor, 1,3 dimethyl-6-(2-propoxy-5-methane sulphonylamidophenyl)-pyrazolo[3,4-d]pyrimidin-4-(5H)-one (DMPPO) in phenylephrine-precontracted rat aortic rings and different in vivo rat preparations. 2. DMPPO elicited a concentration (...) with DMPPO (5 mg kg-1, i.v.) partially inhibited the pressor response to phenylephrine (0.3 to 100 micrograms kg-1). 8. In conclusion, the potent and selective PDE 5 inhibitor, DMPPO, produces relaxation in isolated vessels in the presence of a cyclic GMP drive and reduces blood pressure of intact animals. Its high oral bioavailability and long duration of action should make it a useful tool to study the role of cyclic GMP in various biological systems.

1996 British journal of pharmacology

6560. Evidence for the presence of essential histidine and cysteine residues in platelet cGMP-inhibited phosphodiesterase. Full Text available with Trip Pro

Evidence for the presence of essential histidine and cysteine residues in platelet cGMP-inhibited phosphodiesterase. Camp is a major regulator of platelet function. cGMP-inhibited phosphodiesterase (cGI-PDE) is the predominant platelet enzyme hydrolysing cAMP. The pH-rate profile plot for this enzyme yields pKa values of 6.5 and 9.0, consistent with histidine and cysteine residues respectively. Diethyl pyrocarbonate (DEP) inactivates cGI-PDE in a time- and concentration-dependent manner (...) possesses two essential histidine residues for activity, two additional histidines for cGMP inhibition, and one cysteine residue at the active site.

1996 Biochemical Journal

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