INT49850

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Context Info
Confidence 0.58
First Reported 1993
Last Reported 2010
Negated 1
Speculated 3
Reported most in Body
Documents 105
Total Number 115
Disease Relevance 76.91
Pain Relevance 26.59

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

cytosol (PDE4A) signal transduction (PDE4A) plasma membrane (PDE4A)
nucleus (PDE4A) cytoplasm (PDE4A)
Anatomy Link Frequency
lung 9
macrophages 3
synovial cells 2
lymphocytes 2
neutrophils 2
PDE4A (Homo sapiens)
Pain Link Frequency Relevance Heat
Inflammation 2852 99.92 Very High Very High Very High
adenocard 163 99.92 Very High Very High Very High
agonist 682 99.70 Very High Very High Very High
cytokine 923 99.68 Very High Very High Very High
Norepinephrine uptake inhibitor 1 99.66 Very High Very High Very High
cINOD 204 99.60 Very High Very High Very High
antagonist 328 99.50 Very High Very High Very High
rheumatoid arthritis 231 99.16 Very High Very High Very High
depression 28 99.16 Very High Very High Very High
metalloproteinase 19 98.96 Very High Very High Very High
Disease Link Frequency Relevance Heat
INFLAMMATION 3302 99.92 Very High Very High Very High
Pulmonary Disease 3798 99.88 Very High Very High Very High
Vomiting 391 99.80 Very High Very High Very High
Targeted Disruption 161 99.76 Very High Very High Very High
Asthma 2372 99.62 Very High Very High Very High
Diarrhoea 169 99.48 Very High Very High Very High
Premature Birth 51 99.28 Very High Very High Very High
Cognitive Disorder 149 99.20 Very High Very High Very High
Rheumatoid Arthritis 231 99.16 Very High Very High Very High
Experimental Arthritis 90 99.16 Very High Very High Very High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
PDE4 inhibition reduced cyclooxygenase-2 protein expression and PGE(2) production and also modulated MMP-9, a key mediator of the membrane rupture process, by inhibiting pro-MMP-9 mRNA expression and pro-MMP-9 activity.
Negative_regulation (inhibition) of PDE4 associated with rupture
1) Confidence 0.58 Published 2005 Journal J. Immunol. Section Abstract Doc Link 15944316 Disease Relevance 0.74 Pain Relevance 0.47
PDE4 selective inhibitors are currently in clinical trials for the treatment of diseases related to inflammatory disorders.
Negative_regulation (inhibitors) of PDE4 associated with inflammation and disease
2) Confidence 0.58 Published 2007 Journal BMC Pregnancy Childbirth Section Abstract Doc Link PMC1892053 Disease Relevance 0.49 Pain Relevance 0.16
On this model of explants, we demonstrated that PDE4 selective inhibitors diminished greatly the production of TNF?
Negative_regulation (inhibitors) of PDE4
3) Confidence 0.58 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.41 Pain Relevance 0.25
Very recently, we demonstrated that PDE4 inhibition prevents in vivo preterm delivery and fetal demise in mice [12].
Negative_regulation (inhibition) of PDE4 associated with premature birth
4) Confidence 0.58 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.64 Pain Relevance 0.20
BACKGROUND: It has been previously demonstrated that diazepam inhibits the cyclic nucleotide phosphodiesterase type 4 isozyme (PDE4).
Negative_regulation (inhibits) of PDE4
5) Confidence 0.58 Published 2004 Journal Clin Ther Section Abstract Doc Link 15220017 Disease Relevance 0 Pain Relevance 0.09
These data suggest that PDE4 inhibitors would not be expected to have significant bronchodilator efficacy when administered alone (Engelstatter et al 2005) and in allergic asthma, roflumilast demonstrated very modest activity in preventing acute bronchoconstriction to allergen challenge (Van Schalkwyk et al 2005) which is in stark contrast to the well known bronchoprotective activity of ?
Negative_regulation (inhibitors) of PDE4 associated with asthma
6) Confidence 0.54 Published 2007 Journal International Journal of Chronic Obstructive Pulmonary Disease Section Body Doc Link PMC2695611 Disease Relevance 0.35 Pain Relevance 0.14
BACKGROUND: It has been previously demonstrated that diazepam inhibits the cyclic nucleotide phosphodiesterase type 4 isozyme (PDE4).
Negative_regulation (inhibits) of cyclic nucleotide phosphodiesterase type 4 isozyme
7) Confidence 0.50 Published 2004 Journal Clin Ther Section Abstract Doc Link 15220017 Disease Relevance 0 Pain Relevance 0.09
Selective inhibition of PDE4 activity affected LPS signaling, because PDE4 inhibitors (rolipram and/or cilomilast) reduced the release of the proinflammatory cytokine TNF-alpha and increased the release of the anti-inflammatory cytokine IL-10.
Negative_regulation (inhibitors) of PDE4 associated with inflammation and cytokine
8) Confidence 0.43 Published 2005 Journal J. Immunol. Section Abstract Doc Link 15944316 Disease Relevance 0.75 Pain Relevance 0.49
Selective inhibition of PDE4 activity affected LPS signaling, because PDE4 inhibitors (rolipram and/or cilomilast) reduced the release of the proinflammatory cytokine TNF-alpha and increased the release of the anti-inflammatory cytokine IL-10.
Negative_regulation (inhibition) of PDE4 associated with inflammation and cytokine
9) Confidence 0.43 Published 2005 Journal J. Immunol. Section Abstract Doc Link 15944316 Disease Relevance 0.76 Pain Relevance 0.49
Two hours after surgery, vehicle or the PDE4 selective inhibitor, rolipram, was injected in the peritoneal cavity and the frequency of preterm delivery and the fetal demises were recorded 48 h post-surgery.
Negative_regulation (inhibitor) of PDE4 in peritoneal cavity associated with premature birth
10) Confidence 0.43 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.70 Pain Relevance 0.23
Application of a PDE4 inhibitor potentiates the effect of ?
Negative_regulation (inhibitor) of PDE4
11) Confidence 0.43 Published 2007 Journal BMC Pregnancy Childbirth Section Body Doc Link PMC1892053 Disease Relevance 0.10 Pain Relevance 0.18
CONCLUSION: In this preliminary study, diazepam increased cAMP plasma levels in anesthetized patients, presumably through inhibition of PDE4 activity.


Negative_regulation (inhibition) of PDE4 in plasma
12) Confidence 0.42 Published 2004 Journal Clin Ther Section Body Doc Link 15220017 Disease Relevance 0 Pain Relevance 0
In contrast, nonxanthine-based compounds that selectively inhibit PDE4 do not share these limitations of theophylline, and have undergone extensive preclinical and clinical evaluation.12,21,22 The most advanced compound within this class is the benzamide, roflumilast (see Figure 1), which is being developed jointly by Nycomed (Zurich, Switzerland, formerly Altana) in Europe and the Forest Research Institute in the US (ownership transferred from Nycomed in December 2009) for the treatment of COPD.


Negative_regulation (inhibit) of PDE4 associated with pulmonary disease
13) Confidence 0.42 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.51 Pain Relevance 0.14
Finally, total systemic exposure, estimated from the AUC, exceeds that of roflumilast by about 10-fold.59 Taken together, these data indicate that the N-oxide metabolite accounts for about 90% of the biologic action of roflumilast and produces long-lasting, competitive PDE4 inhibition over 24 hours, making once-daily roflumilast administration a realistic treatment regimen.
Negative_regulation (inhibition) of PDE4
14) Confidence 0.42 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.13 Pain Relevance 0
Indeed, cilomilast and a PDE4 inhibitor from Purdue-Frederick, V-11294A, preferentially inhibit (by 10- and 30-fold, respectively) PDE4D,28,29 which has been linked with gastrointestinal (GI) events of concern that are often associated with this class of drugs.21,30,31 Both of these compounds were discontinued from development because of unfavorable adverse effect profiles and/or lack of efficacy.32 Both roflumilast and its N-oxide are highly selective PDE4 inhibitors, and are essentially inactive against PDEs 1, 2, 3, 5, and 7 at concentrations up to 10 ?
Negative_regulation (inhibitors) of PDE4
15) Confidence 0.42 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.23 Pain Relevance 0.03
Indeed, cilomilast and a PDE4 inhibitor from Purdue-Frederick, V-11294A, preferentially inhibit (by 10- and 30-fold, respectively) PDE4D,28,29 which has been linked with gastrointestinal (GI) events of concern that are often associated with this class of drugs.21,30,31 Both of these compounds were discontinued from development because of unfavorable adverse effect profiles and/or lack of efficacy.32 Both roflumilast and its N-oxide are highly selective PDE4 inhibitors, and are essentially inactive against PDEs 1, 2, 3, 5, and 7 at concentrations up to 10 ?
Negative_regulation (inhibitor) of PDE4
16) Confidence 0.42 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.23 Pain Relevance 0.04
PDE is a generic term that describes a large superfamily of enzymes that catalyze the breakdown of cyclic adenosine-3’,5’-monophosphate (cAMP) and/or cyclic guanosine-3’,5’-monophosphate (cGMP) to their respective inactive nucleotide 5’-monophosphates.11 Eleven distinct PDE families have been identified,11 although most of the anti-inflammatory activity is believed to result from the inhibition of PDE4, for which there is clinical precedent.12 Indeed, theophylline is a weak, nonselective PDE inhibitor (see below) and has been used in clinical practice as a bronchodilator for more than 70 years.
Negative_regulation (inhibition) of PDE4 associated with adenocard and inflammation
17) Confidence 0.42 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 1.15 Pain Relevance 0.35
Roflumilast is the first selective phosphodiesterase 4 inhibitor and will offer physicians another treatment option for patients with more severe COPD.



Negative_regulation (inhibitor) of phosphodiesterase 4 associated with pulmonary disease
18) Confidence 0.42 Published 2010 Journal Drug Des Devel Ther Section Abstract Doc Link PMC2915539 Disease Relevance 0.53 Pain Relevance 0.09
Regardless of the outcome of those talks, in the European Union at least, after more than 20 years of development, roflumilast will become the first class PDE4 inhibitor for the treatment of COPD and will provide physicians with another treatment option for patients with more severe disease.



Negative_regulation (inhibitor) of PDE4 associated with pulmonary disease and disease
19) Confidence 0.42 Published 2010 Journal Drug Des Devel Ther Section Body Doc Link PMC2915539 Disease Relevance 0.55 Pain Relevance 0
Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.
Negative_regulation (inhibitors) of PDE4 in lung associated with pulmonary disease, inflammation and disease
20) Confidence 0.42 Published 2005 Journal Mem. Inst. Oswaldo Cruz Section Abstract Doc Link 15962112 Disease Relevance 1.03 Pain Relevance 0.45

General Comments

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