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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The non-hydrolysable cyclic AMP analogue, dibutyryl (Bu2)-cyclic AMP, inhibited the stimulated release of histamine from both basophils and human lung mast cells (HLMC) in a dose-dependent manner. The concentrations required to inhibit histamine release by 50% (IC50) were 0.8 and 0.7 mM in basophils and HLMC, respectively. The cyclic GMP analogue, Bu2-cyclic GMP, was ineffective as an inhibitor of histamine release in basophils and HLMC. 2. The non-selective phosphodiesterase (PDE) inhibitors, theophylline and isobutyl-methylxanthine (IBMX) inhibited the IgE-mediated release of histamine from both human basophils and HLMC in a dose-dependent fashion. IBMX and theophylline were more potent inhibitors in basophils than HLMC. IC50 values for the inhibition of histamine release were, 0.05 and 0.2 mM for IBMX and theophylline, respectively, in basophils and 0.25 and 1.2 mM for IBMX and theophylline in HLMC. 3. The PDE 4 inhibitor, rolipram, attenuated the release of both histamine and the generation of sulphopeptidoleukotrienes (sLT) from activated basophils at sub-micromolar concentrations but was ineffective at inhibiting the release of histamine and the generation of both sLT and prostaglandin D2 (PGD2) in HLMC. Additional PDE 4 inhibitors, denbufylline, Ro 20-1724, RP 73401 and nitraquazone, were all found to be effective inhibitors of mediator release in basophils but were ineffective in HLMC unless high concentrations (1 mM) were employed. 4. Neither 8-methoxymethyl IBMX (PDE 1 inhibitor), zaprinast (PDE 5 inhibitor) nor a range of PDE 3 inhibitors (siguazodan, SKF 94120, SKF 95654) were effective inhibitors of mediator release from either basophils or HLMC. 5. In basophils, rolipram acted to potentiate the inhibitory effects of the adenylate cyclase activator, forskolin, whereas in HLMC, rolipram failed to potentiate the inhibitory effects of forskolin. 6. Extracts of purified HLMC and basophils hydrolysed cyclic AMP. IBMX (100 microM) inhibited the PDE activity in basophil extracts by 67 +/- 7% (P < 0.0001) and in HLMC extracts by 63 +/- 9% (P < 0.0005). The hydrolysis of cyclic AMP by basophil extracts was inhibited by the selective PDE inhibitors (all at 10 microM), rolipram (56 +/- 8%, P < 0.0001) and the mixed PDE 3/4 inhibitor, Org 30029 (47 +/- 9%, P < 0.01), whereas 8-methoxymethyl IBMX, siguazodan and zaprinast were ineffective. In HLMC, rolipram, Org 30029, 8-methoxymethyl IBMX, siguazodan and zaprinast all inhibited the hydrolysis of cyclic AMP by extracts to a significant (P < 0.05) and similar extent (approximately 25% inhibition at 10 microM). 7. In total, these data suggest that modulation of the PDE 4 isoform can regulate basophil responses whereas an association of the PDE 4 isoform with the regulation of HLMC function remains uncertain.
...
PMID:Effects of phosphodiesterase inhibitors on human lung mast cell and basophil function. 915 39

Human peripheral blood basophils are known to secrete interleukin (IL)-4 and IL-13 after cross-linking of cell surface IgE. However, little is known about the pharmacological regulation of allergic cytokine release from basophils. In the present study, we investigated the effects of cyclic 3',5'-adenosine monophosphate (cAMP)-elevating agents on antigen-induced IL-4 and IL-13 release from basophil-enriched leukocyte preparations. We obtained venous blood from 27 atopic asthmatic patients (mean age was 45.8+/-3.6 years, all patients were sensitive to mite antigen) and prepared basophil-enriched leukocyte preparations by double-Percoll gradients (basophil purity was 13.4+/-1.6%). The cell preparations were treated with phosphodiesterase (PDE) inhibitors, dexamethasone, forskolin or dibutyryl cAMP for 10 min and were challenged with mite antigen for 6 h. The released IL-4 and IL-13 in the supernatants were measured by enzyme-linked immunosorbent assay systems. No IL-4 or IL-13 was detected in the supernatant of the basophil-depleted preparation after the challenge with mite antigen, suggesting that basophils specifically produce these cytokines. A nonselective PDE inhibitor, theophylline, and a PDE IV-selective inhibitor, rolipram, significantly suppressed the release of IL-4 and IL-13 from the basophil-enriched preparation. Although several concentrations of cilostazol, a PDE III-selective inhibitor, had no effect on the release of both cytokines, cilostazol suppressed the release of IL-4 additively when applied with rolipram. Forskolin and dibutyril cAMP also significantly suppressed the release of both cytokines, suggesting that the suppressive effects by PDE inhibitors were accompanied by the elevations in cAMP levels. We conclude that basophil-enriched leukocyte preparations produce IL-4 and IL-13 in response to antigen and that the release of these cytokines could be regulated by cAMP-modulating agents.
...
PMID:Cyclic AMP-elevating agents inhibit mite-antigen-induced IL-4 and IL-13 release from basophil-enriched leukocyte preparation. 941 38

Atopic dermatitis is the most common chronic skin disease of young children and is frequently associated with asthma and allergies. Th2-type cytokine secreting T cells expressing the cutaneous lymphocyte-associated antigen play a central role in the induction of local IgE responses and recruitment of eosinophils in this disease. Chronic inflammation in atopic dermatitis likely involves a number of interdependent factors, including repeated or persistent exposure to allergens, which can lead to Th2-cell expansion. In addition, exotoxins secreted by Staphylococcus aureus acting as both superantigens and allergens can contribute to persistent inflammation or exacerbations of atopic dermatitis. Treatment of atopic dermatitis with topical agents such as tacrolimus ointment and phosphodiesterase-4 inhibitors offers new approaches directed at correction of the immune dysfunction associated with this disease.
...
PMID:Advances in the understanding and treatment of atopic dermatitis. 942 90

Human basophils have recently been shown to rapidly produce and release interleukin (IL-)4 and IL-13 as well as histamine and eicosanoids. Since both IL-4 and IL-13 can initiate and maintain late phase allergic reactions we addressed whether some widely used anti-allergic drugs can inhibit the anti-IgE induced release of these cytokines from enriched human basophils. Basophils were enriched (47-92% purity) by Ficoll density centrifugation followed by elutriation and negative selection of contaminating cells using immunomagnetic beads. Basophils were stimulated with sub-optimal dilutions of anti-IgE in the presence or absence of various drugs and the release of histamine and cytokines were measured after 30 min and 4 h, respectively. The beta-2 agonist salmeterol, the H1-receptor antagonist terfenadine and the phosphodiesterase inhibitor theophylline inhibited the release of IL-4 and IL-13 by more than 50% following 4 h of basophil stimulation with anti-IgE. These drugs also inhibited the release of histamine following 30 min stimulation, although with less efficacy than for IL-4 and IL-13. Short preincubation of basophils with salmeterol or terfenadine before stimulation gave rise to significantly greater inhibition of histamine release but had less effect on the inhibition of cytokine release. The effects of theophylline, however, were not significantly affected by preincubation of the cells with the drug. In contrast to the aforementioned drugs, salbutamol and cetirizine were ineffective at inhibiting both histamine and cytokine release from basophils. These results suggest that a number of anti-allergic drugs may mediate their effects, in part, in reducing late phase allergic responses due to their actions on IL-4 and IL-13 secretion from basophils.
...
PMID:Inhibition of interleukin-4 and interleukin-13 release from immunologically activated human basophils due to the actions of anti-allergic drugs. 965 Aug 12

Until the recent introduction of long acting beta 2-agonists and the leukotriene antagonists, the drug treatment of asthma had remained largely unchanged for a quarter century. Recent studies have demonstrated the efficacy of the long acting beta 2-agonists in the management of asthma in children and highlighted their value as an adjunct to inhaled corticosteroids. The leukotriene antagonists are an important new class of drug therapy which target a specific area of asthma pathogenesis. Whilst they have been shown to be effective for asthma, their exact role in the clinical situation remains to be established. Recent guidelines have emphasised the important role of inflammation in persistent asthma and recommended the early institution of anti-inflammatory treatment. Many patients remain uncontrolled despite high doses of anti-inflammatory agents including oral corticosteroids. Recent experience with other immunomodulatory agents such as cyclosporin, methotrexate and intravenous immunoglobulin has highlighed their potential as steroid sparing agents. With improved understanding of asthma pathogenesis the potential for specific targeted therapies has become evident. Monoclonal antibodies to IgE and certain cytokines are being investigated as possible treatments for asthma. Similarly, preliminary studies of selective phosphodiesterase inhibitors in asthmatic individuals have been encouraging. Other potential therapies include platelet-activating factor receptor antagonists, tryptase inhibitors and prostaglandin E analogs. The continued development of such targeted treatments should ensure a greater diversity of therapeutic options for the management of asthma in the new millennium.
...
PMID:Asthma--the changing face of drug therapy. 1083 43

Non-selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) block allergen-induced contraction of passively sensitized human airways in vitro by a dual mechanism involving a direct relaxant effect on smooth muscle and inhibition of histamine and cysteinyl leukotriene (LT) release from airways. We investigated the effects of non-selective PDE inhibitors and selective inhibitors of PDE3 and PDE4 in order to determine the involvement of PDE isoenzymes in the suppression of allergic bronchoconstriction. Macroscopically normal airways from 76 patients were sensitized with IgE-rich sera (>250 u ml(-1)) containing specific antibodies against allergen (Dermatophagoides farinae). Contractile responses of bronchial rings were assessed using standard organ bath techniques. Passive sensitization caused increased contractile responses to allergen, histamine and LTC(4). Non-selective PDE inhibitors (theophylline, 3-isobutyl-1-methylxanthine [IBMX]), a PDE3-selective inhibitor (motapizone), PDE4-selective inhibitors (RP73401, rolipram, AWD 12-281) and a mixed PDE3/4 inhibitor (zardaverine) all significantly relaxed inherent bronchial tone at resting tension and to a similar degree. Theophylline, IBMX, zardaverine and the combination of motapizone and RP73401 inhibited the contractile responses to allergen and LTC(4). Pre-treatment with motapizone, RP73401, rolipram or the methylxanthine adenosine receptor antagonist, 8-phenyltheophylline, did not significantly decrease responses to either allergen or LTC(4). We conclude that combined inhibition of PDE3 and PDE4, but not selective inhibition of either isoenzyme or antagonism of adenosine receptors, is effective in suppressing allergen-induced contractions of passively sensitized human airways. The relationship between allergen- and LTC(4)-induced responses suggests that PDE inhibitors with PDE3 and PDE4 selectivity are likely to act in part through inhibition of mediator release and not simply through direct relaxant actions on airway smooth muscle.
...
PMID:The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways. 1113 38

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulairtrade mark, Merck) and zafirlukast (Accolatetrade mark, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflotrade mark, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.
...
PMID:Leukotriene inhibitors and non-steroidal therapies in the treatment of asthma. 1133 68

Asthma bronchiale represents a major health issue in industrialized countries and will likely remain so for decades. The drug treatment of asthma demonstrates certain peculiarities: revolutionary new drug introductions happen almost each quarter century. With improved understanding of asthma pathogenesis and drug metabolism, the potential for specific targeted and constructed therapies has become evident. Monoclonal antibodies to IgE and certain cytokines such IL-4 and IL-5 are being investigated as possible treatments for asthma. Similarly, preliminary studies of selective phosphodiesterase inhibitors in asthmatic patients have been encouraging. Other potential therapies include for example inhibitors of cytokine synthesis, promoters of Th2-Th1 switch, adenosine receptor agonists or antagonists, etc.. A new way is represented by a modified retrometabolic drug design resulting in so-called soft drugs. The first representative of this new drug class is loteprednol etabote (LE), a non-fluorinated glucocorticoid approved for the allergic ophthalmological indications and now in clinical trial for the treatment of allergic airway diseases. Today's intensive search for new treatments should ensure a greater diversity of therapeutic possibilities for the management of asthma in the new millennium.
...
PMID:Drug therapy in asthma bronchiale in the new millennium. 1187 94

The prevalence of asthma and other allergic disorders has been on the increase not only in the western world but also in the developing countries. This increasing prevalence has lead research into the discovery and development of various new therapeutic strategies. The improved understanding about the pathophysiology of asthma has prompted the developments of novel molecules to tackle this problem. These include newer phosphodiesterase inhibitors, cytokine modulation strategies, allergen immunotherapy, and anti-IgE. Immunoglobulin E plays a major role in airway inflammation in asthma. Omalizumab, a novel humanised monoclonal antibody directed against the high affinity FcepsilonRI portion of the IgE has shown a lot of promise in the control of asthma symptoms and as a steroid sparing agent in the management of allergic asthma. This new molecule has an excellent safety profile and could play an important role in the management of patients with severe asthma. This review gives a brief overview of the newer therapies under investigation with special reference to omalizumab in the treatment of allergic asthma.
...
PMID:Newer therapies for asthma: a focus on anti-IgE. 1202 49

Bronchial asthma is one of the most common chronic diseases in modern society and yet, despite the availability of highly effective drugs, there is increasing evidence to suggest that its incidence is increasing. It is a general health problem in several industrialised countries and will remain one for the next decades. With regard to asthma pathogenesis, our understanding has increased tremendously over the last two decades. Therefore, the potential for specific targeted and constructed therapies has become evident. Monoclonal antibodies to IgE, soluble receptors or antibodies to certain cytokines such as IL-4 and IL-5 are being investigated as possible treatments for asthma. Besides the already known receptor antagonists, new compounds directed to novel receptor types (e.g. cytokine, adenosine, adhesion molecules, etc.) are now under development. New targets in the cytosol will come into focus. Preliminary studies of selective phosphodiesterase (PDE) inhibitors in asthmatic patients have been encouraging. It is also very likely that the use of glucocorticoids cannot be excluded from therapy. However, we should generate new glucocorticoids with less side-effects, probably by using the so-called retrometabolic drug design. The first representative of this new steroid class, loteprednol is already approved for the therapy of certain allergic disorders. Because asthma is a disease of many different gene polymorphisms, gene therapy seems to be of low success at present. Alternatively, antisense oligonucleotides could be used. Future developments may also include strategies targeting the remodeling of structural elements of the airways. Today's intensive search for new treatments should ensure a greater diversity of therapeutic possibilities for the management of asthma in the next millennium.
...
PMID:Asthma therapy in the new millennium. 1208 67


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---