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)

We have investigated the bronchodilator and anti-inflammatory properties of roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide), a novel, highly potent, and selective phosphodiesterase 4 (PDE4) inhibitor. Additionally, we compared the effects of roflumilast and its N-oxide, the primary metabolite in vivo, with those of the PDE4 inhibitors piclamilast, rolipram, and cilomilast. Roflumilast inhibited the ovalbumin-evoked contractions of tracheal chains prepared from sensitized guinea pigs (EC(50) = 2 x 10(-7) M) but showed no relaxant effect on tissues contracted spontaneously. In spasmogen-challenged rats and guinea pigs, intravenously administered roflumilast displayed bronchodilatory activity (ED(50) = 4.4 and 7.1 micromol/kg, respectively). Furthermore, roflumilast dose dependently attenuated allergen-induced bronchoconstriction in guinea pigs (ED(50) = 0.1 micromol/kg i.v.). Roflumilast given orally (ED(50) = 1.5 micromol/kg) showed equal potency to its N-oxide (ED(50) = 1.0 micromol/kg) but was superior to piclamilast (ED(50) = 8.3 micromol/kg), rolipram (ED(50) = 32.5 micromol/kg), and cilomilast (ED(50) = 52.2 micromol/kg) in suppressing allergen-induced early airway reactions. To assess the anti-inflammatory potential of orally administered roflumilast, antigen-induced cell infiltration, total protein, and TNFalpha concentration in bronchoalveolar lavage fluid of Brown Norway rats were determined. Roflumilast and its N-oxide equally inhibited eosinophilia (ED(50) = 2.7 and 2.5 micromol/kg, respectively), whereas the reference inhibitors displayed lower potency (ED(50) = 17-106 micromol/kg). Besides, orally administered roflumilast abrogated LPS-induced circulating TNFalpha in the rat (ED(50) = 0.3 micromol/kg), an effect shared by its N-oxide, with both molecules exhibiting 8-, 25-, and 310-fold superiority to piclamilast, rolipram, and cilomilast, respectively. These results, coupled with the in vitro effects of roflumilast on inflammatory cells, suggest that roflumilast represents a potential new drug for the treatment of asthma and chronic obstructive pulmonary disease.
...
PMID:In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. 1125 55

We studied whether selective inhibitors of cyclic nucleotide hydrolysing phosphodiesterase (PDE) isoenzymes influence IL-1beta-induced nitric oxide (NO) release from human articular chondrocytes. In addition, the pattern of PDE isoenzymes contributing to cyclic nucleotide hydrolysis in human chondrocytes was characterized. Chondrocytes were isolated from human osteoarthritic cartilage and cultured in alginate beads. IL-1beta-induced chondrocyte products (nitric oxide and prostaglandin E(2)) were measured in culture supernatants after 48 h incubation time. PDE activities were assessed in chondrocyte lysates. Inducible nitric oxide synthase (iNOS) and PDE4A-D proteins were detected by immunoblotting. The selective PDE4 inhibitors Piclamilast and Roflumilast partially attenuated IL-1beta-induced NO production whereas selective inhibitors of PDE2 (EHNA), PDE3 (Motapizone) or PDE5 (Sildenafil) were inactive. Indomethacin reversed the reduction of IL-1beta-induced NO by PDE4 inhibitors. It was shown that autocrine prostaglandin E(2) (PGE(2)) enabled PDE4 inhibitors to reduce IL-1beta-induced NO in this experimental setting. Major PDE4 and PDE1 activities were identified in chondrocyte lysates whereas only minor activities of PDE2, 3 and 5 were found. IL-1beta and cyclic AMP-mimetics upregulated PDE4 activity and this was associated with an augmentation of PDE4B2 protein. Based on the view that nitric oxide contributes to cartilage degradation in osteoarthritis our study suggests that PDE4 inhibitors may have chondroprotective effects.
...
PMID:Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes--functional importance of phosphodiesterase 4. 1183 8

The phosphodiesterase 4 inhibitor Roflumilast (B9302-107) (RF) and its metabolite 4-amino-3,5-dichloropyridine (ADCP) produced nasal toxicity in preclinical safety studies with rats. The purpose of this study was to assess the possible formation of DNA adducts, by RF and ADCP, in the nasal mucosa, liver and testes of male rats using the 32P-postlabeling assay. For comparison, rats were exposed to the DNA-reactive carcinogens 2,6-dimethylaniline (DMA), also known as 2,6-xylidine, a nasal carcinogen, and the aromatic amine carcinogens 4,4'-methylene-bis(2-chloroaniline) (MOCA), which yields monocyclic DNA adducts, and 2-acetylaminofluorene (2-AAF). In the case of RF, possible sources of DNA adducts include the parent molecule and its ADCP moiety by enzymatic N-hydroxylation and sulfation, reactions typical of carcinogenic aromatic amines. 4-Acetoxylamino-3,5-dichloropyridine (N-acetoxy-ADCP), a chemically activated derivative of ADCP, was prepared and used to modify DNA which was then used to establish the chromatographic conditions with which to reliably detect whether or not such adducts were formed metabolically from RF and ADCP. Similarly, a standard N-hydroxy-DMA was prepared, but the corresponding N-acetoxy derivative was unstable and decomposed during synthesis. Both N-hydroxy-DMA and N-acetoxy-ADCP were mutagenic in the Salmonella typhimurium Ames assay using strain TA100 without an exogenous bioactivation system, with the former being more potent. N-hydroxy-ADCP was essentially inactive in this assay. For the 32P-postlabeling assay, male Wistar rats were exposed to the test substances and carrier control compounds by intragastric instillation at the selected dose levels for 7 days. Subsequently, the nasal mucosa, liver, and testes of the rats exposed to the test or control compounds were extirpated, the DNA extracted and the samples postlabeled. The patterns of adducts formed with the test compounds were compared to those formed in N-acetoxy-ADCP- and N-hydroxy-DMA-adducted DNA, which were assayed by both nuclease P1 and butanol enhancement methods. Based upon the similarity of results from the two enhancement methods, only the former was used for the in vivo studies. No evidence was obtained for the formation of DNA adducts from RF or its metabolites, specifically ADCP, under the conditions of these assays despite the ability to detect adducts from DNA modified chemically with N-acetoxy-ADCP and DNA adducts from the other compounds in their target organs. In the absence of a pattern of compound-related spots, we conclude that RF does not form DNA adducts having the potential to initiate neoplasia in these three tissues.
...
PMID:Lack of DNA binding in the rat nasal mucosa and other tissues of the nasal toxicants roflumilast, a phosphodiesterase 4 inhibitor, and a metabolite, 4-amino-3,5-dichloropyridine, in contrast to the nasal carcinogen 2,6-dimethylaniline. 1185 Sep 74

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.
...
PMID:The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo. 1186 66

Roflumilast [APTA 2217, B9302-107, BY 217, BYK 20869] is a selective phosphodiesterase IV inhibitor. It is being developed by Altana Pharma (formerly Byk Gulden), a subsidiary of Altana Group, as an orally administered therapy for asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and psoriasis. The drug is awaiting regulatory approval in Europe for the treatment of asthma and COPD. Byk Gulden has stated that roflumilast relieves asthma symptoms through both an anti-inflammatory effect and a muscle relaxant effect. Roflumilast has potential as first-line long-term therapy in mild-to-moderate COPD and as additive long-term therapy in moderate-to-severe COPD. Altana has stated that roflumilast is to be marketed under the brand name Daxas. Altana Group and Pharmacia Corporation (now Pfizer) signed an agreement on 22 April 2002 to collaborate on the development and commercialisation of roflumilast for the treatment of respiratory disorders, including asthma and COPD. The companies will jointly develop the drug for the US, Europe and other markets. Pharmacia will co-ordinate development in the US and Altana will co-ordinate development in Europe. After approval of the drug, Pharmacia and Altana will jointly launch and promote roflumilast in the US, Europe and elsewhere. Altana will receive an upfront payment and additional milestone payments. Altana additionally has the option to co-promote Pharmacia products in the US and elsewhere. On 16 April 2003, Pharmacia Corporation was acquired by, and merged into, Pfizer. In November 2002, Altana and Tanabe Seiyaku signed an agreement to collaborate on the development and commercialisation of roflumilast for the treatment of respiratory diseases, including asthma and COPD. Tanabe Seiyaku and Altana will develop roflumilast for asthma and COPD in Japan, and will jointly launch and co-promote roflumilast in Japan following regulatory approval. Roflumilast has been in multinational phase III clinical studies in Europe for the treatment of asthma and COPD. In September 2003, Altana announced the completion of a phase III trial in COPD in more than 1400 patients; the trial showed positive results. In the US, roflumilast is in phase III trials for the treatment of asthma and phase II trials for the treatment of COPD. Phase I clinical trials of roflumilast were begun in Japan by Tanabe Seiyaku in the fourth quarter of 2003. Altana has stated that roflumilast has shown significant superiority over placebo in the treatment of asthma in phase II trials. The efficacy of the drug appears to be comparable to low-dose inhaled corticosteroids in the treatment of asthma and at least equal to inhaled corticosteroids in the treatment of COPD. Altana Group presented data from phase II trials in 516 patients with COPD at an analyst meeting [August 2001, Bad Homburg, Germany] that showed that roflumilast 500 microg/day significantly improved FEV(1) at 24 weeks compared with placebo. In March 2004, Altana Pharma presented pharmacokinetic data from a phase I trial of roflumilast at the 60th Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2004) [San Francisco, CA, USA]. This open-label, randomised, two-period crossover study investigated the pharmacokinetics of oral roflumilast and its active metabolite, roflumilast N-oxide, among 12 healthy male subjects. Participants received single doses of oral roflumilast 500 microg and intravenous (i.v) roflumilast 150 microg as a 15-min short-term infusion. In November 2002, the combined global market for asthma and COPD products was estimated to be worth >11 billion US dollars. In Japan, products in this market segment reached sales of approximately 1.5 billion US dollars in 2001. Roflumilast has patent protection in Europe and Japan until 2014 and in the US until 2015. The Financial Times in April 2002 claimed that roflumilast is an 'important' product for Altana, due to be listed on the New York Stock Exchange later in the same month. The Altana chairman confirmed that the company had been in talks with Pfizer, Bristol-Myers Squibb and Novartis with regard to future development and commercialisation of roflumilast. In September 2002, Dow Jones Newswires stated that Altana is to file for European approval of roflumilast 1 year later than initially was expected; however, this has not changed the company's outlook for the product, which was said to remain at at 1 billion Euros. In August 2001, the Financial Times reported that roflumilast, for the indication of smoker's cough alone, has the potential to reach sales of more than 500 million US dollars a year. A future co-marketing deal for roflumilast in the US was said to be "a key step towards expanding Altana's presence in the US".
...
PMID:Roflumilast: APTA 2217, B9302-107, BY 217, BYK 20869. 1513 82

Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD). The therapeutic ratio for PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (emesis). The two main orally active PDE4 inhibitors in the late phase III of clinical development are cilomilast and roflumilast; the latter (and its active metabolite N-oxide) is more selective and potent with a superior therapeutic ratio. Studies on cilomilast in COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with cilomilast 15 mg twice daily and roflumilast 500 mug once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function. Roflumilast has a better safety and tolerability profile than cilomilast, with the main adverse effects being nausea, diarrhoea, and abdominal pain. Roflumilast also has activity in asthma as assessed by its attenuation of allergen and exercise challenges, and it shows clinical efficacy equivalent to that of beclomethasone dipropionate 400 mug daily. The emerging results of clinical trials on PDE4 inhibitors in asthma and COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory therapy for asthma and COPD and their place in management guidelines. Ultimately, clinicians will want to know whether PDE4 inhibitors are anything more than expensive "designer" theophylline, the archetypal non-selective phosphodiesterase inhibitor.
...
PMID:Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. 1563

Roflumilast, a potent and selective phosphodiesterase 4 (PDE4) inhibitor, has been demonstrated to be an effective anti-inflammatory agent in airway inflammatory diseases. In the present study, we investigated the mechanism of anti-inflammatory effects of roflumilast in murine macrophage cell line RAW264.7 cells. Roflumilast inhibited NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta production via suppression of their gene expressions in lipopolysaccharide (LPS)-stimulated macrophages. To elucidate the mechanism by which roflumilast inhibits the production of inflammatory mediators, we examined the effect of roflumilast on the activation of nuclear factor-kappaB (NF-kappaB) in these cells. Roflumilast inhibited the DNA binding activity of NF-kappaB by preventing inhibitor kappaBalpha phosphorylation and degradation. The phosphorylation of mitogen-activated protein (MAP) kinases, including stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, was also markedly inhibited by roflumilast. Similar to the effects of roflumilast, treatment of either SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole] or SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone], specific inhibitors of p38 MAP kinase and JNK, respectively, suppressed NO, TNF-alpha, and IL-1beta production. Consistent with in vitro results, administration of roflumilast recovered the survival rate of LPS-treated mice, with concurrent suppression of plasma levels of nitrite/nitrate, TNF-alpha, and IL-1beta. These results suggest that the inhibitory activity of roflumilast on the production of inflammatory mediators seems to be mediated via inhibition of NF-kappaB, p38 MAP kinase, and JNK activation in macrophages.
...
PMID:Roflumilast inhibits lipopolysaccharide-induced inflammatory mediators via suppression of nuclear factor-kappaB, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase activation. 1612 38

Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1h before OVA challenge with roflumilast (0.3, 1.0, and 3.0mg/kg), rolipram (0.8, 2.8, and 8.3mg/kg), piclamilast (10.0, 20.0, and 30.0mg/kg), or cilomilast (10.3, 34.3, and 103.0mg/kg). Airway hyperresponsiveness (AHR) against adenosine was investigated by measuring airway resistance 200min after OVA challenge. Subsequently, neutrophil influx and tumor necrosis factor-alpha (TNF-alpha) release in the lungs were determined by bronchoalveolar lavage. Direct bronchodilation at the time point of AHR assessment by PDE4 inhibitors was examined in serotonin-challenged animals. Evaluation of neutropenic animals or treatment with anti-TNF-alpha antibody revealed that AHR was independent of neutrophil accumulation or TNF-alpha release. Roflumilast (50% inhibitory dose [ID(50)]=1.5mg/kg) inhibited AHR 3-, 16-, and 27-fold more potently than rolipram, piclamilast, and cilomilast, respectively. Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID(50)=0.9mg/kg) than rolipram (ID(50)=6.9mg/kg), piclamilast (ID(50)=28.1mg/kg), or cilomilast (ID(50)=37.7mg/kg). Roflumilast, rolipram, and piclamilast-but not cilomilast-suppressed OVA-induced TNF-alpha release in a dose-dependent manner. Roflumilast (ID(50)=0.9mg/kg) exhibited 9- and 23-fold more potent inhibition of TNF-alpha release than rolipram and piclamilast, respectively. Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects. This study suggests that roflumilast has anti-inflammatory action and provides rationale for the investigation of roflumilast in asthmatic patients.
...
PMID:Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors. 1625 50

Roflumilast is an inhibitor of phosphodiesterase- IV (PDE4), a cellular enzyme that is linked to airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). In clinical trials, roflumilast produced significant improvements in FEV1 (forced expiratory volume in one second) and PEF (peak expiratory flow) compared with low-dose inhaled beclomethasone in asthma patients, and compared with placebo in COPD patients. Roflumilast reduced the use of rescue medication in both populations. COPD patients on roflumilast experienced fewer exacerbations. The most common adverse effects reported in roflumilast trials were diarrhea, nausea, headache, and abdominal pain. Evidence is only available in non-peer-reviewed format abstracts. Most of the measures used are markers of clinical effects as opposed to clinical outcomes. More studies are needed to determine the role of roflumilast in the treatment of asthma and COPD.
...
PMID:Roflumilast for asthma and chronic obstructive pulmonary disease. 1631 27

Roflumilast is a selective phosphodiesterase (PDE) 4 inhibitor with a range of anti-inflammatory properties and potential for treatment of inflammatory disease. The therapeutic effects of roflumilast are thought to be mediated via increased levels of cellular 3',5'-cyclic adenosine monophosphate (cAMP) and include inhibition of microvascular leakage, inhibition of trafficking, release of cytokines and chemokines from inflammatory cells, and bronchodilation. The anti-inflammatory and bronchodilator properties of roflumilast have resulted in clinical studies to investigate the effects of roflumilast in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. In asthma, roflumilast taken as a once-daily oral dose of 500 ug has been shown to improve clinical symptoms and airway function, reduce exercise-induced asthma and decrease bronchial airway hyperresponsiveness. In chronic obstructive pulmonary disease, roflumilast taken as a once-daily oral dose of 500 ug has been shown to reduce the frequency of exacerbations with small effects on improving lung function. Side effects of roflumilast appear to be mild and short lasting. It is likely that this new class of selective PDE4 inhibitor may provide a therapeutic option for patients with inflammatory airway disease.
...
PMID:Roflumilast: a selective phosphodiesterase 4 inhibitor. 1638 9


1 2 3 4 5 6 7 8 Next >>

---