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)

Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW 755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz (alpha adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW 755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.
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PMID:Effect of selected antiinflammatory agents and other drugs on zymosan, arachidonic acid, PAF and carrageenan induced paw edema in the mouse. 312 May 10

The effect of antiinflammatory drugs, phosphodiesterase inhibitors, leukotriene and mediator antagonists and other drug classes were evaluated in a PAF-induced mortality model in mice. By the oral route of administration (-1 hr), dapsone (ED50 = 25 mg/kg), BW 755C (ED50 = 29 mg/kg), theophylline (ED50 = 30 mg/kg) and LY-171,883 (ED50 = 50 mg/kg) protected against PAF-induced lethality in the mouse. Other drugs that afforded protection when given at various dosing schedules and routes were NDGA (100 mg/kg, -18 hr p.o.), diphenyldisulfide (100 mg/kg, -18 hr p.o.), diphenyldisulfide (200 mg/kg, -18 hr p.o.), dexamethasone (1 mg/kg, -3 hr p.o.), dipyridamole (2 mg/kg, -2 min i.v.) and kadsurenone (10 mg/kg, -2 min i.v.). Nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin were inactive and the combination of AA-861, a putative 5-LO inhibitor, and indomethacin also failed to prevent PAF-induced lethality. Therefore, our pharmacological data do not consistently support the notion that PAF-induced lethality is due unequivocally to leukotrienes derived from 5-lipoxygenase metabolism.
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PMID:Pharmacologic modulation of PAF-induced mortality in mice. 312 May 13

Compounds from two distinct pharmacological classes namely, SK&F 86002 and pentoxifylline, were examined for their effects on TNF alpha and IL-1 beta release by human monocytes stimulated with LPS or monoclonal antibodies to three cell surface glycoproteins, CD44, CD45 and LFA-3 (LFA-3 is also known as CD58). SK&F 86002, an inhibitor of 5-LO and CO in arachidonic acid metabolism, inhibited LPS-induced release of TNF alpha and IL-1 beta with an IC50 of 1 microM. At this dose, it also inhibited by > 50%, release of both cytokines induced by the three monoclonal antibodies. Pentoxifylline, a methylxanthine derivative with phosphodiesterase inhibitory activity, selectively inhibited LPS-induced TNF alpha release with an IC50 of 100 microM. TNF alpha and IL-1 beta release mediated by the monoclonal antibodies were inhibited by less than 30% in the presence of 100 microM pentoxifylline. These results suggest that (a) LPS induced cytokine release shares a common step with the physiologically relevant stimuli (involving cross-linking of cell surface receptors), and that this pathway is sensitive to inhibition by SK&F 86002 and, (b) SK&F 86002 is more potent than pentoxifylline in inhibiting TNF alpha and IL-1 beta release induced by both stimuli.
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PMID:Inhibition of CD44, CD45 and LFA-3 mediated cytokine release from human monocytes by SK&F 86002 and pentoxifylline. 768 99

Biomarkers such as C-reactive protein (CRP) and myeloperoxidase (MPO) are elevated in patients with coronary artery disease and confer risk of acute cardiovascular events, such as myocardial infarction (MI) and stroke. More recently, variants in the 5-lipoxygenase-activating protein (FLAP) gene were shown to confer risk to both MI and stroke, effects that appear to be mediated through elevated LTB(4), a chemoattractant mediator shown to be upregulated in patients with MI. Another gene in the leukotriene (LT) pathway, LTA(4) hydrolase, was subsequently found to confer increased risk to MI, effects that were ethnicity-specific with an approximately threefold higher risk in African Americans than in whites. In another study, markers in the phosphodiesterase (PDE) 4D gene were found to confer risk to large-vessel occlusive and cardiogenic stroke. Interestingly, there is a cross-link between the 5-LO and the PDE4D pathways with converging biology. To address the role of an inhibitor of FLAP on biomarkers of MI risk, a randomized placebo-controlled phase II trial was conducted in patients with MI. This trial showed that LTB(4) and MPO production was reduced in whole blood leukocytes that were stimulated with ionomycin and the effects of the inhibitor were dose dependent. Serum CRP and plasma MPO were also reduced at the highest dose, which was well tolerated. These data suggest that LTB(4) is a risk factor of MI and that inhibition of FLAP and the LT pathway produces suppression of biomarkers that are associated with MI risk, including but not limited to LTB(4), MPO, and CRP, supporting the notion that the LTB(4) arm of the LT pathway may play a fundamental role in heart attacks and stroke.
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PMID:Role of FLAP and PDE4D in myocardial infarction and stroke: target discovery and future treatment options. 1663 37