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)

[2-Cyano-3-(methylamino)phenylamino]oxoacetic acid, sodium salt (Wy-41,195) was found to be a potent oral inhibitor (viz., ED50, 0.3 mg/kg) of IgE-mediated release in the rat passive cutaneous anaphylaxis (PCA) model and was very effective by the aerosol and oral route in the rat passive lung anaphylaxis model. High doses (25-50 mg/kg p.o.) were effective when administered up to 180 min before antigen challenge in the rat PCA model. The compound had minimal phosphodiesterase activity and demonstrated no bronchodilator or antihistamine activity. In the dog, Wy-41,195 inhibited histamine-induced reflex bronchoconstriction but had little effect on Ascaris-induced bronchoconstriction. No significant ancillary pharmacology was observed for Wy-41,195 except for inhibition of gastric secretion in the rat. The compound is relatively nontoxic and possesses a very high therapeutic index (greater than 10 000). Activity in these animal systems indicates that Wy-41,195 may hold promise in the treatment of bronchial asthma and other allergic diseases in man.
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PMID:The pharmacologic profile of wy-41,195, a new orally effective antiallergic agent. 618 61

The action mechanism of the bronchodilator activity of BB-1502 was studied in comparison with aminophylline. Orally administered BB-1502 did not inhibit passive cutaneous anaphylaxis in rats, an immediate allergic reaction of Type I, but strongly protected the same antigen-mediated anaphylactic asthma by the intraduodenal route, the activity being approximately 13 times more potent than that of aminophylline. BB-1502 also inhibited IgG-mediated anaphylactic asthma in guinea pigs by the oral route. Both IgE- and IgG-mediated histamine releases from rat lung were similarly inhibited by BB-1502, the potency being 2--3 times that of aminophylline. Disodium cromoglycate showed specific inhibition of the IgE-mediated reaction. BB-1502 and aminophylline showed nonspecific inhibition of the spasms of guinea pig ileum elicited by histamine, acetylcholine and BaCl2. Both compounds inhibited cyclic AMP and cyclic GMP phosphodiesterases (PDEs) derived from guinea pig organs. BB-1502 specifically inhibited the cyclic AMP PDE of lung and brain origins, while aminophylline showed no such specificity. The results of the present study suggested that the bronchodilator and anti-asthmatic actions of BB-1502 might, at least in part, be due to the regulation of cyclic nucleotide PDEs.
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PMID:[Experimental study on the action mechanism of a new bronchodilator agent, BB-1502]. 620 Apr 10

Isolated human granulocytes secrete the lysosomal enzyme beta glucuronidase when incubated with complement-activated zymosan particles. Isoproterenol inhibits this release, and the beta adrenergic response is associated with an increase in granulocyte cyclic adenosine monophosphate (cAMP) levels. In asthma, the beta adrenergic responsiveness is impaired. Cyclic AMP concentration in the granulocyte is also influenced by phosphodiesterase hydrolysis of this cyclic nucleotide. We found that the potent phosphodiesterase inhibitor, RO 20-1724, inhibited zymosan-stimulated beta glucuronidase release from granulocytes in a dose-dependent fashion (10(-8) to 10(-4) M). The inhibition of lysosomal enzyme release by RO 20-1724 was associated with an increase in granulocyte cAMP. Granulocytes were also isolated from asthmatic patients and the RO 20-1724 inhibition of beta glucuronidase release was compared with the response in normal subjects. The negative log molar median effective dose (ED50) value (mean +/- SE) was 5.98 +/- 0.69 in normal subjects and 5.90 +/- 0.63 in asthmatics. These observations suggest that the granulocyte metabolism modulated by the RO 20-1724-sensitive phosphodiesterase is equally responsive to this potent phosphodiesterase inhibitor in normal and asthmatic leukocytes.
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PMID:The granulocyte response to the phosphodiesterase inhibitor RO 20-1724 in asthma. 625 24

The content of cAMP, cGMP and cAMP phosphodiesterase activity were studied in lymphocytes of bronchial asthma patients and normal persons before and 15 min after euphylline administration in a dose of 4 mg/kg. The cAMP/cGMP ratio was significantly lowered in patients. Euphylline administration led to its significant increase. In normal persons, this ratio remained unchanged. Some patients manifested an elevated activity of cAMP phosphodiesterase. In these cases, administration of euphylline brought about a significant increase in cAMP level in lymphocytes in the presence of the lowered activity of the enzyme phosphodiesterase. In the remaining patients and in normal persons, these indicators did not significantly change. It is suggested that the mechanism of euphylline action is dependent on cAMP phosphodiesterase activity.
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PMID:[Effect of euphylline on the cyclic nucleotide content and cAMP phosphodiesterase activity of the lymphocytes of bronchial asthma patients]. 632 15

A 17 year old male with a history of bronchial asthma was admitted to the intensive care unit in severe respiratory distress. During a two week period of intensive respiratory care he received large doses of aminophylline and corticosteroids. In addition, pancuronium was given to facilitate ventilation and to reduce airway pressure. Large doses of pancuronium, as much as 5 mg/hr, were required to stop spontaneous respiratory efforts and restlessness. The total pancuronium dose given during the two week period was 800 mg. One hour after pancuronium was discontinued the patient could open his eyes and move his lips. Peripheral nerve stimulation indicated partial paralysis which improved promptly following a test dose of edrophonium. The authors speculate the aminophylline, which is a known inhibitor of the enzyme phosphodiesterase, raised the level of c-AMP and, in turn, the level of acetylcholine at the neuromuscular junction and thus antagonized the blocking effect of pancuronium. In addition, the large doses of corticosteroids that the patient had received may have enhanced the release of acetylcholine and further facilitated neuromuscular transmission.
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PMID:Resistance to pancuronium in an asthmatic patient treated with aminophylline and steroids. 707 8

Therapeutic response to theophylline in asthma is generally attributed to its effect in increasing intracellular 3',5' cyclic adenosine monophosphate (cAMP) by competitive inhibition of cAMP phosphodiesterase. However, because of discrepancies between therapeutic serum theophylline concentration achieved clinically and those required for in vitro phosphodiesterase inhibition, we explored the possibility that theophylline may act through adrenomedullary secretion of catecholamines. Five healthy, nonasthmatic male and female adults were studied with a double-blind, randomized, crossover protocol. Theophylline (5 mg/kg) and placebo were administered in a capsule dosage form. Plasma catecholamines epinephrine (E), norepinephrine (NE), and dopamine (DA) were measured by a radioenzymatic assay at baseline and after administration of theophylline at 1, 2, and 3 hr. Significant differences between theophylline- and placebo-treated groups (p less than 0.05) were seen at 3 hr for mean percentage increase over baseline with E (120% +/- 25.3%) and NE (48.02% +/- 17.94%) after theophylline therapy (mean peak level 7.2 +/- 0.48 micrograms/ml). Epinephrine plasma concentration was significantly greater (p less than 0.001) at 3 hr compared with baseline (105 +/- 16 vs 56 +/- 18 pg/ml), while NE (448 +/- 52 vs 320 +/- 36 pg/ml) did not attain significance (p = 0.136). A significant correlation (p less than 0.05) was found between the percentage increase over basal for E (r = 0.58) and NE (r = 0.66) and serum theophylline levels. DA was not significantly increased at any time period. Thus theophylline in clinically relevant concentration appears to stimulate adrenomedullary secretion of catecholamine. Whether this is an important mechanism of action in asthma or explains some side effects of theophylline remains to be determined.
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PMID:Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects. 713 May 53

We studied the effect of cilostazol, a cyclic nucleotide phosphodiesterase (PDE) III inhibitor, on a substance P (SP)-induced increase in lung resistance and in airway microvascular leakage in guinea pigs in vivo. Four minutes after intravenous (i.v.) administration of cilostazol (1.5 and 5 mg/kg) or vehicle, Evans blue dye (20 mg/kg) was given i.v. One minute later, 30 nmol/kg SP was administered i.v. The SP-induced increase in lung resistance was measured for 6 min. Following the measurement of lung resistance, microvascular leakage at the trachea, main bronchi and intrapulmonary airways was also examined. Cilostazol attenuated the SP-induced increase in lung resistance, with a significant inhibition at the concentration of 5 mg/kg. Five milligrams per kilogram cilostazol also significantly inhibited SP-induced Evans blue dye extravasation at the trachea and main bronchi. These results suggest that cilostazol might reduce airflow obstruction which is seen in diseases such as asthma through attenuation of bronchoconstriction and, possibly, airway edema resulting from airway microvascular leakage in man.
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PMID:Effects of cilostazol, a cyclic nucleotide phosphodiesterase III inhibitor, on substance P-induced airflow obstruction and airway microvascular leakage in guinea pigs. 751 49

The effects of selective phosphodiesterase (PDE) isoenzyme inhibitors on eosinophil airway infiltration induced by intratracheal administration of recombinant human cytokines were investigated in the guinea pig. Recombinant human IL-5 and IL-8 elicited a concentration-dependent increase in the number of eosinophils in the bronchoalveolar lavage (BAL) fluid. In contrast, no effect was observed after intratracheal injection of recombinant human IL-3 or recombinant human RANTES. Pretreatment with the PDE IV inhibitors rolipram or Ro 20-1724 or the nonselective PDE inhibitor theophylline 1 h before intratracheal injection of IL-5 significantly reduced the number of eosinophils in the BAL fluid at 48 h. In contrast, the selective PDE III inhibitors milrinone and SK&F 94-836 and the PDE I/V inhibitor zaprinast did not inhibit the airway eosinophil infiltration induced by IL-5. Betamethasone also significantly inhibited the IL-5-induced eosinophil infiltration in BAL fluid. Administration of rolipram or betamethasone 1 h before IL-8 significantly reduced airway eosinophil infiltration. Because the selective PDE IV inhibitors markedly inhibited eosinophil infiltration in guinea pig airways induced by cytokines, it is suggested that PDE IV inhibitors have antiinflammatory effects in the airways and may be useful in the treatment of asthma.
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PMID:Modulation of cytokine-induced eosinophil infiltration by phosphodiesterase inhibitors. 753 26

The effects of AH 21-132, a type III and IV phosphodiesterase (PDE) inhibitor, on allergic reactions in the airway were studied by comparing them with the effects of rolipram, a type IV PDE inhibitor, and aminophylline, a non-selective PDE inhibitor. The following results were obtained: 1) AH 21-132, rolipram and aminophylline inhibited the antigen-induced contraction of isolated guinea pig tracheal muscle in vitro. 2) AH 21-132 and aminophylline inhibited antigen-induced histamine release from human lung tissue fragments. 3) Antigen-induced accumulation of inflammatory cells including eosinophils and macrophages in mice bronchoalveolar lavage fluid was clearly inhibited by AH 21-132 and rolipram, but not by aminophylline. 4) AH 21-132, rolipram and aminophylline inhibited immediate phase bronchocostriction induced by either an intravenous or an aerosol challenge of antigen in guinea pigs. 5) AH 21-132 and rolipram inhibited the aeroantigen challenge-induced late phase increase in the airway resistance in guinea pigs, but aminophylline did not. These results suggest that AH 21-132 has an anti-allergic effect in the airway and that these actions may be beneficial for the treatment of allergic bronchial asthma.
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PMID:Studies on anti-allergic action of AH 21-132, a novel isozyme-selective phosphodiesterase inhibitor in airways. 754 55

Theophylline and related xanthines have been used in the treatment of airways diseases such as bronchial asthma for over 50 years. The therapeutic effectiveness of this class of drugs was traditionally thought to be derived from their ability to elicit bronchodilation, however evidence is accumulating to suggest that theophylline in particular possesses immunomodulatory and anti-inflammatory activity. The molecular mechanisms of action of theophylline have not yet been clarified, although several putative mechanisms of action have been proposed. One of these suggests that theophylline via non-selective inhibition of the phosphodiesterase (cAMP) and cyclic guanosine monophosphate (cGMP) levels resulting in relaxation of airway smooth muscle and inhibition of inflammatory cell activation. To date seven different families of the PDE enzyme have been defined according to a variety of criteria including substrate specificity, sensitivity to selective inhibitors and the effect of allosteric modulators. The type IV isoenzyme is the predominant isoenzyme in most inflammatory cells. This article reviews some of the in vitro, in vivo and clinical studies which have demonstrated that theophylline and selective PDE inhibitors possess anti-inflammatory and immunomodulatory activity.
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PMID:Immunomodulatory actions of xanthines and isoenzyme selective phosphodiesterase inhibitors. 755 Feb 9


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