Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

YM976 is a novel and specific phosphodiesterase 4 inhibitor. In our previous report, we indicated that YM976 has less emetogenicity, a major adverse effect of PDE4 inhibitors, than rolipram. In the present study, we examined the antiasthmatic effects of YM976 in guinea pigs. YM976 orally administered exhibited inhibition of antigen-induced bronchoconstriction, airway plasma leakage, airway eosinophil infiltration, and airway hyperreactivity (AHR), with ED(50) values of 7.3, 5.7, 1.0, and 0.52 mg/kg, respectively. Rolipram also dose dependently suppressed these responses. Prednisolone suppressed eosinophil infiltration and AHR, whereas it failed to inhibit bronchoconstriction and plasma leakage. Theophylline moderately suppressed bronchoconstriction and edema, but neither eosinophil infiltration nor AHR. YM976 suppressed the peroxidase activity in the bronchoalveolar lavage fluid, and elevated the intracellular peroxidase activity and cAMP contents of infiltrated cells, suggesting that YM976 inhibited not only the infiltration but also the activation of leukocytes. In vitro studies revealed that YM976 potently suppressed eosinophil activation (EC(30) = 83 nM), and exerted a little relaxation on LTD(4)-precontracted tracheal smooth muscle (EC(50) = 370 nM). Rolipram exhibited a potent tracheal relaxation activity (EC(50) = 50 nM). In vivo studies indicated that the inhibitory effect of YM976 on LTD(4)-induced bronchospasm was marginal even at 30 mg/kg p.o., although rolipram significantly inhibited the bronchospasm at the same dose. These results suggested that YM976, unlike rolipram, showed the inhibition of antigen-induced airway responses due to anti-inflammatory effects, but not to direct tracheal relaxation. In conclusion, YM976 may have potential therapeutic value in the treatment of asthma through its anti-inflammatory activities.
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PMID:Antiasthmatic effect of YM976, a novel PDE4 inhibitor, in guinea pigs. 1125 41

The purpose of this study was to evaluate the efficacy of rolipram, a phosphodiesterase (PDE) 4 inhibitor, in a mouse model of dermatitis induced by repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB). BALB/c mice were sensitized with 0.3% w/v TNCB applied to the ear on day -7, followed by application three times a week from day 0. Rolipram, prednisolone and cyclosporine A were administered orally once daily from day 0 to 21. Rolipram at a dose of 10 mg/kg/day significantly inhibited the ear thickness and the increase in cytokine levels and enzyme activity in the ear. Interleukin (IL)-4 production was markedly decreased in cervical lymph node cells from animals treated with rolipram at a dose of 10 mg/kg/day. Prednisolone and cyclosporine A significantly reduced ear thickness. These compounds significantly decreased the total cell and lymphocyte number of the cervical lymph nodes. Furthermore, prednisolone markedly suppressed body weight gain, and cyclosporine A significantly increased the serum total IgE concentration compared with that in the vehicle-treated control. Rolipram, unlike prednisolone and cyclosporine A, did not influence body weight and the total IgE concentration in the serum. The present results suggest that the PDE4 inhibitor is a promising oral medicine for the treatment of chronic skin inflammatory diseases.
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PMID:Effect of orally administered rolipram, a phosphodiesterase 4 inhibitor, on a mouse model of the dermatitis caused by 2,4,6-trinitro-1-chlorobenzene (TNCB)-repeated application. 1644 96

Eosinophils play a major role in the development and severity of asthma. Robust and rapid preclinical animal models are desirable to profile novel therapeutics inhibiting the influx of eosinophils into the airways. To develop a rapid, airway eosinophil recruitment model in the rat, Brown-Norway (BN) rats were immunised with ovalbumin (OVA)/alum on day 0, 1 and 2 and challenged with OVA aerosol on day 5 and 6. On day 7 bronchoalveolar lavage fluid (BALF) was analysed for eosinophil numbers, eosinophil peroxidase (EPO) activity and cytokines. Lung sections were also examined. The immunised animals showed a strong selective influx of eosinophils into the airways correlating with enhanced EPO activity, Interleukin (IL-4), IL-5 and monocytes chemo attractant protein levels in the BALF in comparison to sham-sensitised rats. In addition the immunised rats developed goblet cell metaplasia in the lung and showed OVA specific IgG1 and IgE levels in the serum but no airway hyperreactivity after metacholine challenge. Airway inflammation was suppressed by applying the steroids Budesonide (intra tracheally) and Prednisolone (per orally), Roflumilast a phosphodiesterase-4 inhibitor, and the H1 receptor antagonists Epinastine and Ketotifen. Montelukast, a Leukotriene receptor antagonist and Chromoglycate, a mast cell stabiliser, had no effect in this model. In summary, in this novel preclinical rat model therapeutics expected to inhibit the development of airway eosinophilia can rapidly be tested.
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PMID:Development and characterisation of a novel and rapid lung eosinophil influx model in the rat. 1849 Jan 84

ABSTRACT Inflammatory bowel disease (IBD) is a common and chronic gastrointestinal disorder characterized by intestinal inflammation and mucosal tissue damage. Reactive oxygen metabolites (ROMs) play a pathogenic role in IBD. We aimed to examine the protective effect of sildenafil, a cGMP phosphodiesterase inhibitor, in the experimental mouse model of IBD. Intrarectal instillation of acetic acid was used to induce IBD. Prednisolone was used as the standard drug for comparison. Sildenafil was used at doses of 0.75, 1.5, and 3 mg/kg. Biochemicals and macroscopic and microscopic examinations of colonic tissue were performed. Results indicated that activity of myeloperoxidase (MPO) and lipid peroxidation product (TBARS) markers of oxidative stress are increased in acetic acid-treated groups and are recovered by sildenafil pretreatment and prednisolone. Sildenafil- (1.5 and 3 mg/kg) and prednisolone-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared to the acetic acid-treated group. The beneficial effect of sildenafil (3 mg/kg) was comparable to that of prednisolone. It is concluded that sildenafil is helpful in the management of IBD, which is presumably related to its strong antioxidative stress potential mediated through enhanced cGMP. Results of proper clinical trials will determine the possible efficacy of phosphodiesterase-5 inhibitors in human IBD.
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PMID:Beneficial effect of phosphodiesterase-5 inhibitor in experimental inflammatory bowel disease; molecular evidence for involvement of oxidative stress. 2002 Sep 51

A 42-year-old woman presented with fever, dyspnea, lower-leg edema, significant pulmonary congestion, pleural effusion, and severely reduced left ventricular contractions. She was resistant to treatment for heart failure, including catecholamines, furosemide, phosphodiesterase III inhibitors, and human atrial natriuretic peptide, and antibiotics failed to reduce her inflammation. She had renal dysfunction and hypocomplementemia and was positive for anti-nuclear and anti-ds-DNA antibodies. The patient was diagnosed with myocarditis and pleurisy associated with systemic lupus erythematosus (SLE). Prednisolone administration improved her general condition, reducing inflammation and improving left ventricular function. On day 1, an electrocardiography (ECG) revealed a T-wave inversion similar to a T-U complex configuration in leads II, aVF, and V3-6. By day 8, however, ECG showed prolonged corrected QT (QTc) and T-wave alternans (alternating beat-to-beat T-wave patterns) in lead V3-6. Careful ECG monitoring should be used to identify potentially fatal ventricular arrhythmias during the recovery phase of SLE-related myocarditis. <Learning objective: This was a case of significant T-wave alternans (TWA) during recovery from systemic lupus erythematosus (SLE)-related myocarditis. Fatal ventricular arrhythmia appears to be a risk during recovery from myocardial damage caused by SLE. Up to now, there have been no published case reports of TWA during this period. Patients with myocarditis should be carefully monitored for arrhythmia, even after ventricular function and inflammation have improved with prednisolone therapy.>.
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PMID:T-wave alternans in a case with systemic lupus erythematosus-related myocarditis. 3027 27