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)

Eosinophils may play a critical role in asthma and bronchial hyperresponsiveness, yet the effect of theophylline on their function is not certain. We have examined the effects of theophylline on opsonized zymosan-induced superoxide anion (O2-) release from guinea pig eosinophils harvested from the peritoneal cavity and from human eosinophils obtained by differential centrifugation of blood from patients with peripheral eosinophilia. Theophylline at high concentration (10(-3) M) inhibited O2- release by 27.6 +/- 9.4% (mean +/- SEM, p less than 0.05), whereas at clinically relevant concentrations (10(-6) and 10(-5) M), it significantly potentiated this by 26.8 +/- 9.9% (p less than 0.05) and 36.9 +/- 6.3% (p less than 0.01), respectively. 8-phenyltheophylline (10(-7) to 10(-3) M), which like theophylline inhibits adenosine receptors but does not inhibit phosphodiesterase activity, produced potentiation at all concentrations. Preincubation of eosinophils with adenosine deaminase (0.1 U/ml) enhanced O2- release by 72.4 +/- 15.2% (p less than 0.01), whereas addition of adenosine (3 x 10(-8) to 10(-6) M) reversed the potentiation induced by theophylline (10(-5) M) in a concentration-dependent manner. Inhibition was greater with the A2-selective analog N-ethylcarboxamide adenosine than the A1-selective analog phenylisopropyladenosine, suggesting that A2-receptors are involved. In human eosinophils we have demonstrated a similar effect of theophylline and adenosine on O2- release. Our results indicate that therapeutic concentrations of theophylline may potentiate eosinophil activation in vivo by competing with circulating adenosine for eosinophil A2-receptors. This would be consistent with the lack of effect of theophylline on bronchial hyperresponsiveness, which may be related to eosinophilic inflammation.
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PMID:Effect of theophylline and adenosine on eosinophil function. 254 25

We examined the effect of a type IV (rolipram) and a combined type III and IV (Org 20421) isoenzyme-selective phosphodiesterase inhibitor upon allergen-induced pulmonary eosinophil recruitment in sensitised Brown Norway rats. Rats were sensitised with ovalbumin intraperitoneally and later challenged with ovalbumin aerosol which induced a significant increase in the total eosinophil and neutrophil count in bronchovalveolar lavage fluid at 24 hours (from 0.38 +/- 0.12 to 1.36 +/- 0.18 x 10(6), p < 0.01 and from 0.06 +/- 0.01 to 0.33 +/- 0.07 x 10(6), p < 0.01) respectively. Pretreatment with rolipram (30 mumol/kg) and Org 20421 (30 mumol/kg) abolished the eosinophilia and neutrophilia evoked by ovalbumin. We conclude that type IV and possibly type III isozyme phosphodiesterase inhibitors may regulate, directly or indirectly, eosinophil and neutrophil activity and/or those cells responsible for attracting them into the lung.
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PMID:Inhibition of allergen-induced lung eosinophilia by type-III and combined type III- and IV-selective phosphodiesterase inhibitors in brown-Norway rats. 765 90

Aeroallergen-induced infiltration of eosinophils in the bronchoalveolar lavage fluid (BALF) in guinea pigs was used as a marker of bronchial inflammation. Drugs were administered orally 4 h after aeroallergen challenge. Allergic bronchial eosinophilia in guinea pigs was inhibited by orally administered dexamethasone and methylprednisolone. Terfenadine (a newer H1-receptor antagonist), theophylline (a nonspecific phosphodiesterase inhibitor), and salbutamol (a beta 2-agonist) did not influence allergic eosinophilic infiltration. Many of these agents, administered prophylactically, have been reported to suppress allergic eosinophilic infiltration in the BALF of guinea pigs. Methylprednisolone, a steroid, inhibits allergic bronchial eosinophilia regardless of the time of administration; that is, 2 h before or 4 h after aeroallergen challenge. The therapeutic approach used in this study may facilitate drug discovery for bronchial inflammation/asthma.
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PMID:Allergic bronchial eosinophilia: a therapeutic approach for the selection of potential bronchial anti-inflammatory drugs. 811 61

A new long-acting beta 2-agonist, formoterol, has been reported to have a greater efficacy and duration of action in asthmatic patients as compared to conventional beta 2-agonists. We recently demonstrated that formoterol inhibited antigen-induced late asthmatic response (LAR) and accompanying airway eosinophilia in guinea pigs. In this study, we investigated the direct effect of formoterol in vitro on human eosinophil function, focusing on platelet-activating factor (PAF)-induced eosinophil chemotaxis and eosinophil cationic protein (ECP) release. Purified normodense eosinophils were separated by discontinuous gradient from 12 mild asthmatic patients. Formoterol in concentrations of 1-100 microM significantly inhibited PAF-induced eosinophil chemotaxis in a dose-dependent manner with a concentration of drug required to produce 50% inhibition (IC50) of 10.16 microM; % inhibition: 22.9 +/- 13.0% (1 microM), 51.6 +/- 12.7% (10 microM), 75.0 +/- 11.3% (100 microM). When formyl-methionyl-leucyl-phenylamine (FMLP) was used as a chemoattractant, a similar inhibition of eosinophil chemotaxis by formoterol was observed; % inhibition: 13.1 +/- 5.0% (1 microM). 47.7 +/- 7.6% (10 microM), 65.5 +/- 16.5% (100 microM). A conventional beta 2-agonist, salbutamol, at doses to 100 microM did not show any inhibitory effects on PAF-induced eosinophil chemotaxis. Formoterol in concentrations of 1-100 microM also significantly inhibited PAF-induced ECP release from eosinophils; % inhibition: 21.7 +/- 9.0% (1 microM), 39.3 +/- 7.4% (10 microM), 39.6 +/- 8.4% (100 microM). In the presence of phosphodiesterase inhibitors, theophylline or isobutylmethyl xanthine (IBMX), the inhibition by formoterol on PAF-induced ECP release was enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory effects of formoterol on platelet-activating factor induced eosinophil chemotaxis and degranulation. 824 1

The effect of rolipram, an isozyme IV-selective inhibitor of cAMP-specific phosphodiesterase, was evaluated in a guinea pig eye model of tissue eosinophilia. (R)-rolipram was administered by gavage to guinea pigs 1 h prior to topical ocular challenge with a mixture of leukotrienes (LTs) (10 ng LTB4 + 1000 ng LTD4/eye) or with histamine dihydrochloride (1 mg/eye). Conjunctivae were evaluated histologically 6 h after challenge. Eosinophil counts per millimeter of conjunctival epithelium in LT-challenged animals that received (R)-rolipram at dosages of 0.1, 0.3, 1, 3, or 10 mg/kg were reduced by 63, 63, 84, 81 and 90% respectively, compared to LT-challenged controls. Reduction was statistically significant (P < 0.05) at all dosages. Eosinophil counts per millimeter of epithelium in histamine-challenged animals that received 10 mg/kg (R)-rolipram were reduced by 79% compared to histamine-challenged controls (P < 0.01). The results indicate that (R)-rolipram inhibits the response to two distinct classes of mediator in this model of eosinophil infiltration, adding support to the contention that isozyme IV-selective cAMP phosphodiesterase inhibitors offer therapeutic potential for human asthma.
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PMID:cAMP-specific phosphodiesterase inhibitor, rolipram, reduces eosinophil infiltration evoked by leukotrienes or by histamine in guinea pig conjunctiva. 838 69

Rolipram, a phosphodiesterase type 4 (PDE4)-selective inhibitor, has been demonstrated to inhibit antigen-induced pulmonary eosinophilia in guinea pigs and monkeys, suggesting that PDE4-selective inhibitors could be useful for treating asthma. Although the rat is used extensively in preclinical drug development, a pulmonary antiinflammatory effect of PDE4 inhibition has not been demonstrated in this species. Therefore, we examined the effects of rolipram, CI-930 (PDE3-selective inhibitor), zaprinast (PDE5-selective inhibitor) and aminophylline on antigen-induced pulmonary inflammatory cell influx in Brown Norway rats. Two weeks after sensitization rats were exposed to aerosolized ovalbumin and 24 h later bronchoalveolar lavage (BAL) was performed for determinations of total cell counts and cell type differentials. The resulting 10-fold increase in total cell counts was due primarily to an increase in eosinophils (from 0.06 to 11.0 x 10(6)) and neutrophils (from 0.02 to 12 x 10(6)). Rolipram, CI-930 and aminophylline, given p.o. before and after antigen challenge, each completely inhibited eosinophil influx, with B.I.D. ED50 values of 0.5, 0.4 and 39 mg/kg, respectively. Rolipram, CI-930 and aminophylline each completely inhibited neutrophil influx as well, with B.I.D. ED50 values of 0.1, 0.5 and 20 mg/kg, respectively. Denbufylline and milrinone (10 mg/kg p.o.) also inhibited eosinophil and neutrophil influx, consistent with PDE4 and PDE3 inhibition as the mechanisms of action of rolipram and CI-930, respectively. In contrast, zaprinast was inactive at 0.3-30 mg/kg. However, the beta2 agonist salbutamol greatly inhibited antigen-induced pulmonary eosinophilia and neutrophilia, with p.o. B.I.D. ED50 values of 2.1 and 2.3 mg/kg, respectively, indicating that drugs which increase intracellular cAMP levels by one of several mechanisms can inhibit antigen-induced pulmonary inflammation in rats. In conclusion, these results demonstrate that PDE4 inhibitors produce pulmonary antiinflammatory effects in rats. Furthermore, these results suggest that PDE3 inhibitors also can produce pulmonary antiinflammatory effects in vivo.
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PMID:Inhibition of antigen-induced pulmonary eosinophilia and neutrophilia by selective inhibitors of phosphodiesterase types 3 or 4 in Brown Norway rats. 882 Feb 46

Ovalbumin (OvA) inhalation by sensitized guinea-pigs caused a pronounced rise in interleukin (IL)-5 in bronchoalveolar lavage (BAL) fluid at both 3 and 24 h after antigen exposure. The increased levels at 24 h were attenuated by the phosphodiesterase inhibitors Ro 20-1724 and aminophylline and by dexamethasone, all of which also attenuated the concurrent lung eosinophilia. The rise in IL-5 at 3 h was additionally attenuated by the PDE3 inhibitor, siguazodan, which failed to attenuate the eosinophilia at 24 h. These results suggest a pivotal action of these compounds on the later rise in IL-5. Ro 20-1724, aminophylline, siguazodan and dexamethasone attenuated a rise in IL-8 levels in BAL fluid at 3 h and the subsequent neutrophilia at 24 h. There was no increase in plasma ACTH at 3 and 24 h after OvA challenge but cortisol levels were elevated at 3 h. This was inhibited by Ro 20-1724, siguazodan and dexamethasone. Thus, elevation of plasma cortisol does not explain the anti-inflammatory actions of these compounds. Aminophylline, however, did raise plasma cortisol at both 3 and 24 h after antigen challenge which may be an important further mechanism of action for this compound.
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PMID:The potential roles of cytokines, IL-5 and IL-8, and plasma cortisol in the anti-inflammatory actions of phosphodiesterase inhibitors in sensitized guinea-pig airways. 977 91

We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.
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PMID:Antiasthmatic activity of the second-generation phosphodiesterase 4 (PDE4) inhibitor SB 207499 (Ariflo) in the guinea pig. 986 84

This study investigates the role of adrenal-derived catecholamines and corticosterone on the inhibition by rolipram, a phosphodiesterase (PDE)-4 inhibitor, of pulmonary eosinophilia and airway hyperresponsiveness (AHR) in allergic mice. The following experimental groups were studied in mice sensitized and challenged with ovalbumin (OVA): normal, adrenalectomized, propranolol (beta-adrenoceptor antagonist) and metyrapone (corticosterone synthesis inhibitor) treated. These interventions were studied both in the absence and in the presence of rolipram. Eosinophil numbers in the bronchoalveolar lavage (BAL) and AHR to methacholine were measured 24 h after OVA challenge. Treatment of sensitized mice with rolipram (0.3 - 10 mg kg(-1), p.o.), inhibited pulmonary eosinophilia and the AHR to methacholine in OVA-challenged mice. Adrenalectomy increased the number of eosinophils in the BAL of OVA-challenged mice but had no effect on AHR to methacholine. Adrenalectomy attenuated both the rolipram-induced inhibition of BAL eosinophilia and AHR to methacholine in OVA challenged mice. Propranolol (10 mg kg(-1), p.o.) had no effect on the inhibition of eosinophilia by rolipram but attenuated the inhibition of AHR to methacholine in OVA challenged mice. On the other hand, metyrapone (10 mg kg(-1), p.o.) attenuated the inhibition of eosinophilia by rolipram but had no effect on the inhibition of AHR to methacholine in OVA challenged mice. Metyrapone-treatment alone increased the number of eosinophils in the BAL of OVA-challenged mice. These results identify an important role for adrenal-derived catecholamines and corticosterone on the inhibition of pulmonary eosinophilia and AHR by rolipram in allergic mice.
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PMID:Inhibition of pulmonary eosinophilia and airway hyperresponsiveness in allergic mice by rolipram: involvement of endogenously released corticosterone and catecholamines. 1080 86

Representative glucocorticosteroids (GCS) and phosphodiesterase IV (PDE4) inhibitors were compared in several models of pulmonary inflammation ranging in severity. Lung tissue eosinophil peroxidase (EPO) levels rather than bronchoalveolar lavage fluid (BALF) EPO or eosinophil percentages were used to indicate eosinophil recruitment after intratracheal instillation of sephadex beads in rats or nebulized ovalbumin in sensitized guinea pigs. A single oral or intratracheal administration of a GCS was effective against mild and robust sephadex-induced eosinophilia whereas the PDE4 inhibitors evaluated appeared more effective in the milder sephadex models. The GCS were also more effective against sephadex-induced than ovalbumin-induced eosinophilia. The effectiveness of the GCS and PDE4 inhibitors improved when the severity of the ovalbumin-induced eosinophilia was decreased. Multiple day dosing also improved activity. These studies indicated that activity was influenced greatly by administration protocols, the severity of the inflammatory response and possibly the method used for estimating eosinophil recruitment.
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PMID:Effects of several glucocorticosteroids and PDE4 inhibitors on increases in total lung eosinophil peroxidase (EPO) levels following either systemic or intratracheal administration in sephadex- or ovalbumin-induced inflammatory models. 1085 Aug 54


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