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)

Disodium cromoglycate (DSCG) prevents allergic asthma by inhibiting the release of chemical mediators of immediate-type allergic reactions. The mechanism of this action is unclear and prompted us to examine the effect of DSCG on cyclic adenosine 3',5'-monophosphate (cAMP), the implicated regulator of IgE-mediated reactions. We used the peripheral blood lymphocyte as a model to mirror the biochemical events occurring in the allergic shock organs. Isolated peripheral blood lymphocytes from perennial allergic asthmatic children receiving only DSCG had significantly (p less than 0.005) lower phosphodiesterase (PDE) activity (mean 1.05 +/- 0.17 SE per 10(6) cells) than normal individuals (2.93 +/- 0.14) and allergic children receiving methylxanthines (4.08 +/- 0.28) or no medications (3.58 +/- 0.2). DSCG (10 mug/ml) significantly lowered PDE activity in normal lymphocytes (p less than 0.005) in a beef heart extract (p less than 0.001), and 100 mug/ml lowered PDE activity in fetal rabbit lung homogenates (p less than 0.001). DSCG (10 mug/ml) significantly elevated (p less than 0.01) cAMP concentration in normal human lymphocytes (118 +/- 38 vs 30 +/- 10 picomoles cAMP/10(6) lymphocytes). Thus, DSCG appears to inhibit chemical mediator release by increasing intracellular cAMP through the inhibition of cAMP PDE.
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PMID:An action of disodium cromoglycate: inhibition of cyclic 3',5'-AMP phosphodiesterase. 17 50

The pharmacological activity of CR 2039 (4-(1H-tetrazol-5-yl)-N-(4-[1H-tetrazol-5-yl]phenylbenzam ide)) a newly discovered antiallergic compound is described. CR 2039 administered i.m. or i.v. inhibited rat passive cutaneous anaphylaxis (PCA) with an ED50 of 0.1 mg/kg and a potency about 15 times higher than that of disodium cromoglycate (DSCG). CR 2039 i.m., by aerosol or as dry powder insufflation, gave dose-related significant protection against IgE-dependent bronchial anaphylaxis induced by aerosolized antigen in anesthetized guinea-pigs. In conscious guinea-pigs CR 2039 given i.m. delayed dose dependently (ED50, 17 mg/kg) the onset of bronchoconstriction induced by aerosolized antigen, while DSCG was ineffective up to 100 mg/kg. The protection was accompanied by significant inhibition of the vascular permeability provoked by antigen challenge in all airway segments except trachea. CR 2039 (10-100 mg/kg i.v.) inhibited the microvascular permeability changes in a model of allergic conjunctivitis in sensitized guinea-pigs. CR 2039 inhibited dose dependently guinea-pig lung cAMP-phosphodiesterase with an IC50 of 50 microM.
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PMID:CR 2039, a new bis-(1H-tetrazol-5-yl)phenylbenzamide derivative with potential for the topical treatment of asthma. 128 5

Patients with atopic dermatitis (AD) have elevated leukocyte cyclic AMP-phosphodiesterase (PDE) activity and increased in vitro IgE synthesis compared to normal (NL) subjects. Interleukin 4 (IL-4), interferon-gamma (IFN-gamma), and PDE inhibitor have been shown to regulate in vitro IgE synthesis. This study investigated whether soluble T-cell factors such as IL-4 and IFN-gamma could account for elevated PDE activity in patients with AD. Both rhIL-4 and IFN-gamma significantly increased normal monocyte PDE activity to a maximum of 188% (n = 6, p less than 0.05) and 315% above control (n = 3, p less than 0.05), respectively. At concentrations below 0.1 units/ml IL-4 and IFN-gamma had synergistic effects on activation of monocyte PDE. AD and NL T-cell culture supernatants also significantly stimulated normal monocyte PDE activity, but the stimulatory activity was not significantly greater in the AD T-cell supernatants. The effect of both cytokines and T-cell supernatants on normal monocytes was inhibited by antibodies against IL-4 and IFN-gamma, respectively. This study demonstrates that IL-4 and IFN-gamma can increase PDE activity in normal monocytes. Though the levels of IL-4 and IFN-gamma in T-cell supernatants are undetectable with an enzyme-linked immunosorbent assay (ELISA) assay, the concentration of these cytokines below the detectable level can significantly increase PDE activity of monocytes in a synergistic and dose-dependent manner. These results suggest that cytokine-mediated activation of monocytes can increase PDE activity. Furthermore, lymphokines may play an important role in modulating the cyclic nucleotide regulatory pathway.
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PMID:Synergistic effects of interleukin 4 and interferon-gamma on monocyte phosphodiesterase activity. 131 7

We attempted to identify and establish the role of cyclic nucleotide phosphodiesterase (PDE) isozymes in human basophils by using standard biochemical techniques as well as describing the effects of isozyme-selective and nonselective inhibitors of PDE. The nonselective PDE inhibitors, theophylline and 3-isobutyl-1-methylxanthine, inhibited anti-IgE-induced release of histamine and leukotriene C4 (LTC4) from basophils. This inhibition was accompanied by elevations in cAMP levels. Rolipram, an inhibitor of the low Km cAMP-specific PDE (PDE IV), inhibited the release of both histamine and LTC4 from activated basophils and increased cAMP levels in these cells. In contrast, mediator release from basophils was not inhibited by either siguazodan or SK&F 95654, inhibitors of the cGMP-inhibited PDE (PDE III) or zaprinast, an inhibitor of the cGMP-specific PDE (PDE V). SK&F 95654 failed to elevate basophil cAMP in these experiments whereas zaprinast induced significant increases in cAMP content. The inhibitory effect of rolipram on mediator release was potentiated by siguazodan or SK&F 95654, but not by zaprinast. SK&F 95654 also enhanced the ability of rolipram to increase cAMP content. Forskolin, a direct activator of adenylate cyclase, inhibited IgE-dependent release of mediators from basophils and increased cAMP levels in these cells. These effects were enhanced by rolipram, but not by SK&F 95654 or zaprinast. The cell permeant analog of cAMP, dibutyryl cAMP, inhibited mediator release from these cells, a property not shared by either dibutyryl-cGMP or sodium nitroprusside, an activator of soluble guanylate cyclase. The presence of both PDE III and PDE IV was confirmed by partially purifying and characterizing PDE activity in broken cell preparations. Overall, these data lend support to the hypothesis that cAMP inhibits mediator release from basophils and suggest that the major PDE isozyme responsible for regulating cyclic AMP content in these cells is PDE IV, with a minor contribution from PDE III. However, the finding that zaprinast caused increases in cAMP without inhibiting mediator release indicates that cAMP accumulation is not invariably linked to an inhibition of basophil activation.
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PMID:Preliminary identification and role of phosphodiesterase isozymes in human basophils. 137 72

LY 186655 (Tibenelast, Lilly) is a new phosphodiesterase inhibitor, not derived from the xanthine, possessing bronchodilating activity in animals. The aim of this work was to study the effect of LY 186655 and theophylline on histamine release from human leukocytes, skin and lung fragments. Histamine was measured using a spectrofluorometric method. Both drugs (3 x 10(-5)-3 x 10(-3) M) exhibited a dose-dependent inhibition on anti-IgE (1/2000)-induced histamine release from human leukocytes. At 3 x 10(-3) M, theophylline was significantly more effective than LY 186655 (mean inhibition 94 and 42%, respectively). On lung fragments, theophylline and LY 186655 (3 x 10(-5)-3 x 10(-3) M) caused strong and comparable inhibitory effects on anti-IgE (1/500)-induced histamine release with a mean inhibition reaching maximally 65%. Histamine release induced by compound 48/80 (1 mg/ml) on sliced human foreskin was reduced with both drugs (3 x 10(-3) M) by about 37%. We conclude that LY 186655 inhibits in vitro immunological histamine release from human lung and cutaneous mast cells as well as basophils with a similar pattern of activity to theophylline.
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PMID:LY 186655, a phosphodiesterase inhibitor, inhibits histamine release from human basophils, lung and skin fragments. 137 45

Several phosphodiesterase (PDE) inhibitors with the capacity to inhibit the PDE IV isoenzyme produce dose-dependent inhibition of IgE-mediated histamine release (HR) from human peripheral leukocytes in vitro. Inhibition reached a maximum after 20 min of preincubation (IC30: 6-30 microM, IC50: 30-80 microM). Motapizone--a potent inhibitor of the isoenzyme PDE III--was much less effective, thus giving indirect evidence that PDE IV plays a predominant role in the control of cAMP cleavage in human basophils. The inhibiting effect of PDE-III/IV-selective compounds on IgE-mediated HR did not exceed the action of PDE-IV-selective inhibitors. The inhibition of anti-IgE-induced HR by zardaverine (a PDE-III/IV-inhibiting compound) was synergistically enhanced in the combined presence of forskolin or the recently synthesized histamine H2-agonist FRA 19).
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PMID:Inhibition of IgE-mediated histamine release from human peripheral leukocytes by selective phosphodiesterase inhibitors. 138 73

Mast cells isolated from human gastric mucosa released histamine on challenge with IgE-directed ligands and calcium ionophores but were essentially unresponsive to a variety of non-immunological stimuli. Moreover, immunologically induced histamine secretion from these cells was inhibited by a number of anti-allergic agents including anti-asthmatic chromones, beta-adrenoceptor agonists and phosphodiesterase inhibitors. In total, these data indicate that mast cells from the human gastric mucosa are in many respects functionally similar to their lung and colonic counterparts.
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PMID:Mast cells from human gastric mucosa: a comparative study with lung and colonic mast cells. 171 23

Atopic dermatitis and the other atopic conditions occur as a result of direct or indirect influences from cells of hematopoietic origin. Cellular immune abnormalities have been described, but appear to be secondary to cutaneous inflammation in atopic dermatitis. Pharmacophysiologic abnormalities are numerous and may relate to defective cyclic nucleotide metabolism in circulating and infiltrating leukocytes. A consistent leukocyte abnormality is elevated cyclic AMP-phosphodiesterase. This enzyme abnormality results in reduced intracellular cyclic AMP, creating a net permissive effect upon cell function. Phosphodiesterase inhibitors have been demonstrated to reduce abnormal histamine release and IgE production by cultured leukocytes. Studies of phosphodiesterase and associated defects in atopic leukocytes may lead to delineation of basic pathogenetic mechanisms as well as providing the potential for therapeutic targeting.
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PMID:Phosphodiesterase and immune dysfunction in atopic dermatitis. 196 82

Atopic dermatitis is transmitted as an autosomal dominant trait. Its expressivity is variable, and flare-ups are triggered by environmental factors such as air-borne allergens, cutaneous flora or foodstuffs. Elevation of serum IgE levels is inconstant and not specific; it is associated with a deficiency of suppressor T cell population. The epidermis contains IgE bound to the surface of Langerhans cells; this abnormality seems to be specific as it is not found in atopic or non atopic healthy subjects. The lack of beta-adrenergic response is partially explained by the hyperactivity of the cyclic AMP-degrading phosphodiesterase. Disturbances in essential fatty acid metabolism (inactivation of delta 6 desaturase) are thought to be responsible for abnormalities in the permeability of epithelial structures. The relationships between pharmacological, biochemical and immunological dysregulations are unknown.
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PMID:[Then physiopathology of atopic dermatitis]. 214 55

Atopic dermatitis, allergic rhinitis and asthma are a common group of diseases with a familial predisposition. At present there is no suitable predictive or diagnostic marker. Adults with atopic dermatitis or allergic respiratory disease have elevated mononuclear leukocyte cAMP-phosphodiesterase activity. This activity correlates closely with histamine release from basophils. We investigated newborn leukocyte phosphodiesterase activity and histamine release in umbilical cord blood. Phosphodiesterase activity was significantly elevated in cord blood leukocytes of 81 children with a positive history of atopy in first degree relatives, compared to 33 children with a negative history (p less than 0.025). In contrast to adults there was no correlation between phosphodiesterase activity and histamine release. Our studies suggest that elevated phosphodiesterase activity is a primary, genetically linked defect. Fetal basophils would appear to possess cytophilic IgE since they are capable of immunologically stimulated histamine release even without passive, in vitro IgE sensitization. In addition, there are functional differences between adult and cord blood basophils. Longitudinal studies may determine if elevated phosphodiesterase is predictive of atopic states.
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PMID:Cyclic AMP-phosphodiesterase activity and histamine release in cord blood leukocyte preparations. 240 31


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