ArticleBritish journal of pharmacology1999
The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor-alpha and leukotriene B4 in a novel human whole blood assay.
Article in British journal of pharmacology, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 69 citations in OpenAlex.
- Pharmacological characterization and preclinical evaluation of 11h: a novel, brain-penetrant PDE4 inhibitor for neurological disorders.Frontiers in pharmacology · 2025Article
- The inflammatory signature in monocytes of Sjögren's syndrome and systemic lupus erythematosus, revealed by the integrated Reactome and drug target analysis.Genes & genomics · 2022Article
- An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022.Molecules (Basel, Switzerland) · 2022Review
- Scope of adjuvant therapy using roflumilast, a PDE-4 inhibitor against COVID-19.Pulmonary pharmacology & therapeutics · 2021Review
- Gram-Negative BacteriaFrontiers in pharmacology · 2021Article
- CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice.Frontiers in pharmacology · 2019Article
- Phosphodiesterase 4 and 7 inhibitors produce protective effects against high glucose-induced neurotoxicity in PC12 cells via modulation of the oxidative stress, apoptosis and inflammation pathways.Metabolic brain disease · 2018Article
- Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance.Brain, behavior, and immunity · 2015Article
- Phosphodiesterase 4-targeted treatments for autoimmune diseases.BMC medicine · 2013Review
- Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.Nature biotechnology · 2010Article
- EMD273316 & EMD95833, type 4 phosphodiesterase inhibitors, stimulate fibroblastic-colony formation by bone marrow cells via direct inhibition of PDE4 and the induction of endogenous prostaglandin synthesis.BMC pharmacology · 2004Article
- Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis.The Journal of clinical investigation · 2002Article
- Assessing the emetic potential of PDE4 inhibitors in rats.British journal of pharmacology · 2002Article
- Distribution and regulation of cyclooxygenase-2 in carrageenan-induced inflammation.British journal of pharmacology · 1999Article
- 5,7-dihydroxy-2-(3-hydroxy-4, 5-dimethoxy-phenyl)-chromen-4-one-a flavone from Bruguiera gymnorrhiza displaying anti-inflammatory properties.Indian journal of pharmacologyArticle
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
1. The aim of this study was to assess the inhibitory activities of phosphodiesterase type 4 (PDE4) inhibitors on tumour necrosis factor-alpha (TNF-alpha) and leukotriene B4 (LTB4) production in a novel human whole blood assay. 2. Lipopolysaccharide (LPS) stimulation of human whole blood caused a time dependent increase in TNF-alpha and prostaglandin E2 (PGE2) plasma levels. Inhibition of LPS-induced TNF-alpha by the selective PDE4 inhibitor RP73401 was proportionally enhanced with endogenous PGE2 (maximal after 24 h). In contrast, blocking endogenous PGE2 production with indomethacin in blood stimulated with LPS for 24 h decreased the potency of RP73401 to that observed with a 4 h LPS incubation. 3. Non-selective and selective PDE4 inhibitors showed greater inhibition of LPS-induced TNF-alpha after 24 h compared to 4 h. Stereoselectivity was only achieved in the 24 h method. 4. LPS-stimulation of whole blood for either 30 min or 24 h followed by N-formyl-Met-Leu-Phe (fMLP) activation resulted in low plasma LTB4 levels. Combination of both treatments resulted in a greater than 7 fold increase in plasma LTB4 levels. Inhibition of the double LPS and fMLP-activated LTB4 production was observed with non-selective and PDE4-selective inhibitors. Their LTB4 inhibitory potencies were similar to that observed in the 24 h LPS-induced TNF-alpha assay. Thus, stimulation of human whole blood with two LPS stimulations followed by fMLP gives rise to both TNF-alpha and LTB4 and their inhibition by various compounds can be assessed in the same blood sample. 5. Calcium ionophore (A23187) stimulation of whole blood resulted in plasma LTB4 levels similar to the double LPS and fMLP method. Inhibition of A23187-induced LTB4 biosynthesis was also achieved by PDE4-selective inhibitors as well as the direct 5-lipoxygenase (5-LO) inhibitor L-739,010. 6. These results confirm the anti-inflammatory properties of PDE4 inhibitors. Thus, this novel human whole blood can be used to assess the biochemical efficacy of PDE4 inhibitors in human subjects.
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