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)

A number of oxamic acid derivatives of tropones and tropolones were synthesized and their antianaphylactic activity was determined in passive paw anaphylaxis (PPA). Several of these esters possessed oral activity. A comparison of the effect on the biological activity of the esters and the corresponding acid and its salt is reported. The experiments suggesting a relationship between the activity and the bioavailability of the ester 19 are also described. A study of the fate of ester 19 in serum on oral or intravenous administration to rats and dogs is reported. In vitro results of the effect of the compounds 19, 45, and 45a on the activity of the guinea pig lung and beef heart phosphodiesterase are presented. The various factors that may contribute to the antiallergy activity of compounds of this series are discussed.
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PMID:Troponoids. 3. Synthesis and antiallergy activity of N-troponyloxamic acid esters. 22 22

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

The antianaphylactic effect of new antihistaminic agents by derivatives of gamma-carboline dimebon and meraboin was studied by the method of passive cutaneous anaphylaxis. It was found that the agents in a dose amounting to 10% of LD50 possessed a high anaphylactic activity which did not correlate with the degree of their antihistaminic effect. During in vitro experiments the mechanism of action of dimebon and meraboin can be conditioned also by their ability to decrease histamine release from mast cells and to reduce the activity of cAMP-dependent phosphodiesterase.
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PMID:[The anti-allergic activity and mechanism of action of gamma-carboline derivatives]. 169 8

Milrinone and sulmazole, two recently developed drugs, inhibit specific fractions of the phosphodiesterase (PDE) isozyme system. Since theophylline aspecifically inhibits the PDE complex, we compared the effects of milrinone and sulmazole with those of theophylline on antigen-induced bronchoconstriction, vasoconstriction, mediator release and leukotriene production. In the isolated perfused and ventilated lung of actively sensitized rats, we elicited antigen-induced bronchoconstriction, vasoconstriction and release of mediators like histamine, 5-hydroxytryptamine (5-HT) and slow-reacting substance of anaphylaxis (SRS-A). Milrinone, sulmazole and theophylline inhibited antigen-induced bronchoconstriction and vasoconstriction in a dose-dependent manner with minor differences in potency. Antigen-induced release of preformed mediators like histamine and 5-HT was inhibited only at high concentrations of milrinone, whereas sulmazole failed to inhibit mediator release. Theophylline also failed to inhibit 5-HT release. However, SRS-A synthesis was markedly reduced by these drugs in relatively low concentrations. It is concluded that milrinone and sulmazole have anti-allergic effects similar to those of theophylline and that all three PDE inhibitors reduce SRS-A synthesis.
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PMID:Anti-allergic effects of milrinone and sulmazole in isolated rat lungs in comparison with theophylline. 247 95

Milrinone and sulmazole, two recently developed cardiotonic drugs, inhibit specific fractions of the phosphodiesterase (PDE) isozyme system, while theophylline inhibits the PDE complex aspecifically. Since these drugs were shown to have anti-allergic effects in isolated lungs, we wanted to study milrinone and sulmazole in comparison with theophylline in an in vivo model of anaphylaxis. For this purpose, actively sensitized rats were intravenously challenged with antigen, while tracheal pressure, oesophageal pressure, blood pressure and airflow were continuously monitored. Antigen challenge induced a transient bronchoconstriction and a persistent fall in blood pressure until death occurred. Anaphylactic shock was consistently followed by metabolic acidosis. Milrinone, 3 mg/kg, and theophylline, 40 mg/kg (but not 10 mg/kg), reduced anaphylactic bronchoconstriction. Sulmazole, 40 mg/kg, almost abolished bronchoconstriction. Although milrinone, sulmazole and theophylline, 40 mg/kg, caused a fall in blood pressure prior to antigen challenge, total fall in blood pressure (drug-induced and antigen-induced) was not affected by these drugs. Surprisingly, sulmazole reduced mortality significantly. This phenomenon is probably related to the less severe metabolic acidosis in the presence of sulmazole.
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PMID:Comparison of the anti-anaphylactic effects of milrinone, sulmazole and theophylline in the rat. 273 94

Components of the cyclic nucleotide system--cAMP, cGMP, activities of adenylate cyclase (AC) and phosphodiesterase (PDase) were studied in brain, lung, adrenal gland, liver tissues, in blood plasma (cAMP, cGMP) and in leukocytes (AC and PDase) of guinea pigs at the periods of sensibilization and development of anaphylaxis. Dibutyryl cAMP was preadministered in a number of the animals in order to correct possible alterations in the system of cyclic nucleotides and to stimulate unspecific resistance of the organism. Distinct alterations were observed in the patterns studied after sensibilization of the animals, especially pronounced in anaphylactic shock. Preadministration of dibutyryl cAMP prevented development of anaphylactic shock in all the animals treated with the antigen. Even after repeated administration of the antigen the antigen. Even after repeated administration of the antigen the anaphylactic shock was observed only in 50% of these animals. The data obtained suggest that synthetic analogues of cAMP may be used for treatment of patients with allergic disorders.
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PMID:[Changes in the cyclic nucleotide system in experimental anaphylaxis and approaches to their correction]. 299 23

BN 52021, a new specific PAF-acether receptor antagonist, was evaluated on several cardiovascular models. BN 52021 antagonized PAF-acether-induced extravasation in rats. Inhibition of the hypotensive action of PAF-acether was obtained by administration of the antagonist, given preventively or curatively. In isolated guinea-pig hearts, BN 52021 inhibited the vasoconstriction induced by PAF-acether whereas a small inhibition was observed with papaverine. On the other hand, phosphodiesterase inhibitors were very effective against coronary vasoconstriction induced by vasopressin while BN 52021 was without effect. PAF-acether increased the tonus of rat isolated portal vein; this effect was inhibited by BN 52021, without any reduction in basal myogenic activity. In this model Ca2+ antagonists (D 600, diltiazem) showed a small inhibitory effect but they strongly reduced basal myogenic activity. Neither PAF-acether nor BN 52021 modified phenylephrine-induced contraction of the isolated rabbit aorta with or without endothelium demonstrating that endothelium-dependent relaxing factor is not related to PAF-acether. Our results suggest that BN 52021 specifically block the cardiovascular effects of PAF-acether. This agent may thus be an useful tool for a better understanding of the role of PAF-acether in hemodynamic changes involved in anaphylaxis or shock.
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PMID:The effects of PAF-acether on the cardiovascular system and their inhibition by a new highly specific PAF-acether receptor antagonist BN 52021. 376 77

[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 of three compounds reported to elevate intracellular cyclic adenosine monophosphate (cAMP) namely 3-isobutyl-1-methylxanthine (IBMX) and prostaglandins D2 and E1 (PGD2 and PGE1), on histamine release was examined. Three test systems were used: (i) the perfused ovalbumin-sensitized guinea pig lung and (ii) isolated cells from ovalbumin-sensitized guinea pig lung, both of which are IgG-mediated models of anaphylaxis, and (iii) an IgE model of anaphylaxis, using isolated rat peritoneal mast cells from sensitized rats. Both PGD2 and PGE1 were without effect at concentrations likely to be found during anaphylaxis. In contrast, the phosphodiesterase inhibitor, IBMX, was highly active in all three test systems. The role of raised intracellular cAMP levels in the inhibition of histamine release is discussed.
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PMID:Action of 3-isobutyl-1-methylxanthine and prostaglandins D2 and E1 on histamine release from rat and guinea pig mast cells. 619

RHC 2963 (7-methyl-pyrido (3',2':4,5)-thieno (3,2-d)-1,2,3 triazine-4(3H)-one and 20 related compounds have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis and for their effects on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells (RMC). Nine compounds were potent (I50 less than or equal to 80 microM) inhibitors of antigen-induced release of histamine (AIR) from RMC, 2 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 60 microM) and one compound inhibited AIR from guinea pig lung slices (I50 = 55 microM). RHC 2963 was 18 times more potent than disodium cromoglycate (DSCG) as inhibitor of AIR from RMC and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties and inability to inhibit non-immunologic release of histamine induced by compound 48/80. Neither RHC 2963 nor DSCG had any effect on anti-IgE-induced release of histamine from human basophils or IgG1-mediated release of histamine from guinea pig lung. Twelve of the compounds in this chemical series were more potent than theophylline as inhibitors of cyclic AMP and/or cyclic GMP phosphodiesterase (PDE) from RMC. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC revealed no statistically significant correlation between the inhibition of AIR and inhibition of cAMP- or cGMP-PDE. We conclude: (1) RHC 2963 and some of the related compounds are potent inhibitors of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG, and (2) inhibition of cAMP- or cGMP-PDE by these compounds is not the biochemical mechanism by which they inhibit AIR from RMC.
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PMID:Antiallergic activity profile in vitro of RHC 2963 and related compounds. 619 98


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