Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Theophylline, a known phosphodiesterase inhibitor, has been widely used as an additional bronchodilator in asthmatic patients who are not adequately controlled on high-doses of inhaled steroids. However, there is growing evidence that theophylline may also have anti-inflammatory or immunomodulatory effects in asthma. This study investigated whether theophylline administration has an impact on serum levels of interleukin (IL)-4 and IL-5 in asthmatic patients. Eight asymptomatic patients aged 30+/-1.5 yrs (mean +/- SEM) with mild atopic asthma were given a single daily dose of theophylline 150 mg or placebo in an on (theophylline)-off (placebo)-on (theophylline)-off (placebo) protocol with a 3-week duration of each on- or off- interval. Determination of serum IL-4 and IL-5 was done at baseline for all subjects and on the last day of each 3-week interval for the patients under study. Serum IL-4 levels were: 35+/-6 (baseline), 19+/-3 (on-1 interval), 29.5+/-4 (off-2), 15+/-2 (on-3) and 26+/-4 pg x mL(-1) (off-4), while IL-5 levels were 27+/-5, 18+/-4, 28+/-5, 17+/-4 and 28+/-5 pg x mL(-1), respectively. Spirometry was unchanged during the study and serum theophylline levels at the end of the two on-periods were 4.5+/-0.05 and 4.2+/-0.07 microg x mL(-1), while all patients remained asymptomatic. In conclusion, the administration of a low, single, daily dose of oral theophylline in asymptomatic patients with mild atopic asthma seems to reduce circulating interleukin-4 and interleukin-5.
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PMID:Theophylline induces a reduction in circulating interleukin-4 and interleukin-5 in atopic asthmatics. 1083 23

Asthma is a common respiratory disorder. It can no longer be viewed as a reversible airway obstruction but should instead be considered primarily as an inflammatory illness that has bronchial hyperreactivity and bronchospasm as its result. There are several potential benefits as well as limitations of the currently available antiasthmatic agents such as anticholinergics, beta 2-selective agonists, methylxanthines, corticosteroids, or mast cell stabilizers. Recent trends in the design of new antiasthmatic agents include isozyme selective phosphodiesterase inhibitors, inhibitors of the biosynthesis of interleukin-4 and IL-4 antagonists, lipoxygenase and leukotriene inhibitors, thromboxane A2 receptor antagonists, potassium channel openers and monoclonal antibodies.
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PMID:Recent perspectives in the design of antiasthmatic agents. 1094 72

Type 4 phosphodiesterase (PDE4) inhibitors reportedly induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Following clinical improvement of one previously untreated CLL patient with sildenafil therapy, we evaluated the in vitro induction of apoptosis in CLL cells by 4 PDE5/6 inhibitors, including sildenafil, vardenafil, zaprinast, and methoxyquinazoline (MQZ). After 24 hours of culture, the various PDE inhibitors differed in their ability to induce apoptosis, with zaprinast displaying no killing effect. Normal B cells isolated from control donors were totally resistant to PDE-induced apoptosis. Vardenafil was 3 and 30 times more potent an inducer of apoptosis than sildenafil and MQZ, respectively. Both vardenafil and sildenafil failed to elevate adenosine 3'5' cyclic monophosphate (cAMP) levels, largely excluding an inhibitory effect on cAMP-PDE3, -PDE4, and -PDE7. Vardenafil- or sildenafil-treated B-CLL cells displayed up to 30% intracellular active caspase 3. Drug-induced apoptosis was inhibited by the caspase inhibitor z-VAD.fmk, prevented by interleukin-4 (IL-4), and significantly reduced by stromal-derived factor1-alpha (SDF-1alpha). We conclude that vardenafil and sildenafil induce caspase-dependent apoptosis of B-CLL cells in vitro and thus might be considered in the treatment of CLL patients. However, further in vivo investigations should be warranted.
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PMID:Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells. 1239 51

In the murine model for respiratory syncytial virus (RSV) infection, cytokine patterns induced by vaccinations with either killed (i.e. formalin-inactivated, alum-precipitated) virus (KV) or live virus (LV) have been shown to influence disease expression. To determine the mRNA expression of the cytokines IL-4 and IFN-gamma in BALB/c mice challenged with RSV, a real-time quantitative reverse-transcriptase PCR assay was developed. This assay uses 5'-exonuclease fluorogenic probes and is performed on the ABI PRISM 7700 Sequence Detector System (TaqMan). The relative quantitative levels of mRNA for IL-4 and IFN-gamma were compared with those measured by an RNase protection assay (RPA) and an enzyme immunoassay (EIA), which are methods used to measure the levels of mRNA and protein, respectively. Results obtained by the TaqMan assay showed that mice primed with KV induces increased IL-4 mRNA production while LV induces increased IFN-gamma mRNA, which is in agreement with conventional methods. IL-4 and IFN-gamma relative quantities obtained from TaqMan were highly correlated to those determined by RPA (r=0.96 for IFN-gamma, P<0.01) and EIA (r=0.90 for IL-4 and r=0.75 for IFN-gamma, P<0.01). Assay reproducibility was examined by testing a same sample in triplicate at three experiments. Minimal deviation values were observed in both intra- and inter-assays. TaqMan, which is rapid, sensitive and reproducible, provides an alternative tool for the quantitative analysis of cytokine mRNA expression in the murine model of RSV immunopathogenesis.
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PMID:Cytokine expression in respiratory syncytial virus-infected mice as measured by quantitative reverse-transcriptase PCR. 1250 27

AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), a phosphodiesterase 4 inhibitor, which is optimized for topical administration, was tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate (TDI). The allergic reaction was challenged by topical administration of TDI onto the mice ears. AWD 12-281 was tested for its anti-inflammatory potential by oral, intraperitoneal and topical administration. The phosphodiesterase 4 inhibitor, cilomilast (SB 207499), and/or the corticosteroid, diflorasone diacetate, were used as reference compounds. Given orally and intraperitoneally 2 h before as well as 5 and 24 h after TDI challenge, AWD 12-281 showed no, or only a transient inhibition of the allergen-induced ear swelling, whereas cilomilast significantly inhibited this ear swelling. Applied topically onto the ears before TDI challenge, AWD 12-281, cilomilast and diflorasone diacetate caused total inhibition of ear swelling 24 h after challenge, confirmed by a decrease of the pro-inflammatory cytokines interleukin-4, interleukin-6 and macrophage inhibitory protein-2. Administered topically after TDI challenge as therapeutic intervention, AWD 12-281 and diflorasone diacetate caused significant inhibition of ear swelling; cilomilast failed to do so. These results indicate that topically administered AWD 12-281 may be potent in the prevention and treatment of allergic/inflammatory skin diseases.
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PMID:AWD 12-281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis. 1295

The aim of the present study was to determine whether inhibition of cyclic nucleotide phosphodiesterase (PDE) modulates the stimulated generation of the cytokines, interleukin-4 (IL-4) and IL-13, from human basophils. This was addressed by evaluating the effects of both nonselective and selective inhibitors of PDEs on the generation of cytokines from basophils. The nonselective PDE inhibitors, isobutyl-methylxanthine (IBMX) and theophylline, attenuated the IgE-mediated generation of IL-4 and IL-13 and, also, the release of histamine from basophils. The effects of the isoform-selective inhibitors, 8-methoxymethyl-IBMX (PDE 1 inhibitor), siguazodan (PDE3 inhibitor), rolipram (PDE4 inhibitor), denbufylline (PDE4 inhibitor), Org 30029 (mixed PDE3 and 4 inhibitor) and zaprinast (PDE5 inhibitor), were studied. Of these selective compounds, only rolipram, denbufylline and Org 30029 inhibited the IgE-dependent generation of IL-4, IL-13 and histamine from basophils to a statistically significant (P<0.05) degree. The effects of isoform-selective inhibitors on basophils activated by IL-3 were evaluated. The IL-3-induced generation of IL-4, IL-13 and histamine was inhibited to a statistically significant (P<0.05) extent, only by compounds that act as inhibitors of PDE4. These data suggest that inhibition of PDE4 can regulate the generation of cytokines from human basophils.
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PMID:Effects of phosphodiesterase inhibitors on interleukin-4 and interleukin-13 generation from human basophils. 1526 10

We investigated the immunoregulatory effects of ibudilast, a nonselective phosphodiesterase inhibitor, at a clinically applicable dose (60 mg/day p.o. for four weeks) in multiple sclerosis (MS) patients. Sensitive real-time PCR for quantifying cytokine mRNA in the blood CD4+ cells revealed that the ibudilast monotherapy significantly reduced tumour necrosis factor-alpha and interferon (IFN)-gamma mRNA and the IFN-gamma/interleukin-4 mRNA ratio, suggesting a shift in the cytokine profile from Th1 toward Th2 dominancy. In a flow cytometric analysis, natural killer T cells, which have been reported to relate to Th2 responses in MS and its animal model (experimental autoimmune encephalomyelitis), increased significantly after the therapy. None of the significant immunological changes were seen in healthy subjects or untreated MS patients. Ibudilast may be a promising therapy for MS and its clinical effects warrant further study.
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PMID:Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. 1547 63

We studied the effect of rolipram, a phosphodiesterase (PDE) IV inhibitor, on allergic footpad swelling in mice. For this study, varying adjuvants including complete Freund's adjuvant (CFA), incomplete Freund's adjuvant (IFA) and Imject Alum (Alum) were used because the extent of antigen-specifically induced T helper type 1 (Th1) and Th2 responses had been shown to depend on adjuvants used. To induce allergic footpad swelling, we immunized mice with ovalbumin (OVA) emulsified in either CFA or IFA, dissolved in Alum or in phosphate-buffered saline (PBS) as a control (day 0), followed by subcutaneous injection of the antigen into footpads on day 21. Rolipram was given orally to the animals daily from days 0-20. Results showed that treatment with rolipram was followed by an increase in early swelling at 0.5 h and a decrease in late swelling at 6 and 24 h in the CFA group. In the IFA group, rolipram significantly enhanced swelling at, but not after, 30 min. In the Alum and the PBS groups, the PDE inhibitor failed to affect the OVA-specific footpad reaction at all times examined. Treatment of the CFA and IFA groups with rolipram significantly inhibited the production of the Th1 antibody anti-OVA immunoglobulin G2a (IgG2a), and the drug enhanced Th2 cell-dependent anti-OVA IgE production. In both groups, rolipram also enhanced the secretion of Th2 cytokines including interleukin-4 (IL-4) and IL-10. These findings suggest that rolipram may facilitate early allergic footpad swelling mediated by Th2 immune responses, while the late phase of swelling associated with Th1 responses may be attenuated by the PDE IV inhibitor.
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PMID:Effect of rolipram, a phosphodiesterase IV inhibitor, on allergic footpad swelling using various adjuvants in mice. 1625 25

Pentoxifylline (PTX) is a nonspecific phosphodiesterase inhibitor which has potent immunoregulatory and antiinflammatory effects. Although its immunomodulation property has been recognized, it is not clear whether PTX could affect dendritic cells (DCs), the most efficient antigen-presenting cells. The purpose of this study was to determine whether PTX could suppress DC differentiation, maturation, and its associated functions. Immature DCs (iDCs) were generated from human peripheral blood mononuclear cell CD14+ monocytes cultured with granulocyte macrophage colony stimulating factor and interleukin-4 for 5 days. PTX concentration-dependently suppressed the expression of iDC differentiation markers including CD54, CD80, CD86, and human leukocyte antigen-DR. In addition, PTX also inhibited DC maturation marker CD83 expression after stimulating DCs with lipopolysaccharide. Furthermore, PTX inhibited the antigen-uptake ability of DCs when tested by fluorescein isothiocyanate-dextran endocytosis assay. PTX significantly reduced the production of TNF-alpha and IFN-gamma in mature DCs (mDCs). Consequently, PTX-treated mDCs showed a reduced activity of mDC-induced T-cell allostimulation and proliferation by mixed-lymphocyte reaction (MLR) assay. Therefore, PTX significantly inhibits CD14+ monocyte-derived DC differentiation, maturation, antigen-uptake ability of iDCs, and antigen-presentation ability of mDCs possibly due to the suppression of TNF-alpha and IFN-gamma production. These results suggested that inhibitory effects of PTX on DCs may contribute its antiinflammatory and immunoregulatory functions.
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PMID:Effects of pentoxifylline on differentiation, maturation, and function of human CD14+ monocyte-derived dendritic cells. 1719 87

As the pathophysiologic process of asthma has become better defined, new molecular targets for treating asthma have emerged. Resident airway cells, circulating leukocytes, and various cell-derived mediators and cytokines contribute to the inflammatory events of asthma. New therapeutic approaches to moderate to severe asthma currently in clinical development include antibodies to IgE and interleukin-5, a soluble receptor that would sequester interleukin-4, cytokine and chemokine receptor antagonists, and phosphodiesterase type 4 inhibitors. Adhesion molecules, which are involved in the migration of inflammatory cells into lung tissue, are also important targets for new antiasthma therapies. Because of researchers' focus on specific pathologic processes and molecular targets, the adverse effects of new agents may be minimized. Also, the longer duration of action of some of the new agents allows weekly to monthly dosing, which may well enhance patient compliance.
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PMID:Treating asthma in the new millennium. 1966 33


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