Disease relevance of DOCEBENONE

• Here, we report that the 5-lipoxygenase metabolites of arachidonic acid activate the pertussis toxin-sensitive G protein-gated muscarinic K+ channel (IK.ACh): arachidonic acid activation of IK.ACh was prevented by the lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861; leukotriene A4 and C4 activated IK.ACh [1].
• Release of obstructive jaundice and simultaneous 70% hepatectomy was performed in rats to study the effect of 5-lipoxygenase inhibitor (AA-861) on liver regeneration [2].
• Pretreatment of the lungs with AA-861, a specific 5-lipoxygenase inhibitor, blocked PAF/protamine-induced leukotriene synthesis, arterial and venous constrictions, and lung edema [3].
• Treatment with AA-861 significantly decreased the leukopenia and thrombocytopenia, and ONO-1078 significantly decreased the hemoconcentration and thrombocytopenia [4].
• The proteinuria, however, could not be reduced by single administration of an inhibitor specific for thromboxane A2 synthase [(E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2, CV-4151)] or for 5-lipoxygenase [2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-1,4-benzoquinone (1, AA-861)] [5].

High impact information on DOCEBENONE

• LTB4 and serum ALT levels were significantly lower after hepatectomy in the rats that were administered AA-861, and a significantly higher LI was observed at 24 hours after hepatectomy in rats receiving AA-861 [2].
• DMSO or AA-861 was administered 24 hours before, during, and 24 hours after hepatectomy in each group [2].
• Inhibition of 5-lipoxygenase pathway by AA-861 or MK 886 inhibited the PAF-induced augmentation of both IL-6 and LTB4 production, suggesting an implication of endogenous leukotrienes in this mechanism [6].
• More modest inhibition was seen with superoxide dismutase (SOD), catalase, the nitric oxide synthase inhibitor monomethyl-L-arginine (L-NMMA), and with inhibitors of the cyclooxygenase (indomethacin), lipoxygenase (AA-861; no effect), and cytochrome P-450 (SKF 525-A) pathways of arachidonic acid metabolism [7].
• Rats were divided into three groups: group I (syngenic orthotopic liver transplantation from LEW to LEW), group II (allogenic OLT from ACI to LEW with dimethyl sulfoxide), and group III (allogenic OLT from ACI to LEW with AA-861 [20 mg/kg/day] s.c. dissolved in DMSO) [8].

Chemical compound and disease context of DOCEBENONE

• This study examined the effect of AA-861, a specific 5-lipoxygenase inhibitor, on brain levels of leukotriene C4 (LTC4) and correlated any changes with changes in edema formation and cerebral blood flow (CBF) after transient ischemia in gerbils [9].
• The effects of 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA-861), a selective 5-lipoxygenase inhibitor, on immunological or non-immunological release of slow reacting substance of anaphylaxis (SRS-A) and histamine and its effects on experimental asthma were investigated [10].
• LTC4/LTB4 alterations in rat forebrain ischemia and reperfusion and effects of AA-861, CV-3988 [11].

Biological context of DOCEBENONE

• The provocative concentration of acetylcholine producing a 20% fall in forced expiratory volume in one second (PC20 FEV1) was measured before and after oral administration of OKY-046 (3000 mg over four days) and AA-861 (1100 mg over four days) and inhalation of OKY-046 (30 mg) in 10, 10, and nine asthmatic subjects respectively [12].
• BW755C, AA-861, nafazatrom, dipyridamole, and propyl gallate did protect and cardiac lipids against oxidative injury in a concentration-dependent manner with respective and antiperoxidant IC50 values (concentrations at which peroxidation was inhibited by 50%) of 0.22, 1.25, 3.0, 3.6 and 50 microM [13].
• We found that these cells express 5-LOX mRNA and we used 3H-thymidine incorporation as a measure of cell proliferation; this was reduced by treating the cultures with 5-LOX inhibitor AA-861 [14].
• AA-861, a 5-lipoxygenase inhibitor, given intrapleurally inhibited the increase in vascular permeability, cell migration, and generation of leukotrienes during the early phase of the pleurisy [15].
• The inhibition of cell proliferation is due to the apoptosis because nuclear condensation and increased annexin V expression were observed in the cells treated with AA-861 and U75302 [16].

Anatomical context of DOCEBENONE

• 5. The lipoxygenase inhibitor AA-861 failed to influence the ability of eosinophils to augment the transmembrane flux of albumin [17].
• The effects of a putatively specific 5-lipoxygenase inhibitor, 2(12-hydroxydodeca-5,10-dinyl)-3,5,6-trimethyl-1,4-benzoquin one (AA-861), and its major metabolite, M-I, were assessed using anti-IgE activated human basophils, lung mast cells and skin mast cells [18].
• In terms of functional aspects, the supernatant of sPLA(2)-IB-stimulated human neutrophils caused chemotactic migration, which was almost completely inhibited by preincubating these cells with three different 5-lipoxygenase inhibitors (MK-886, AA-861, or NDGA) [19].
• To obtain additional information on the mechanisms responsible for anaphylactic release of tachykinins in guinea pig trachea, we examined the effects of phosphoramidon, an inhibitor of neutral endopeptidase, on contractile response to antigen after preincubation with the selective 5-lipoxygenase inhibitor AA-861 [20].
• Both of the edemas were suppressed by pretreatment with mepyramine, methysergide, PAF-antagonists, or dexamethasone, and the latter suppressed by the lipoxygenase inhibitor AA-861, suggesting that histamine, serotonin, PAF, and leukotrienes are involved in exudate formation in these edemas [21].

Associations of DOCEBENONE with other chemical compounds

• That the increased brain water content was causally related to an increase in leukotriene C4 was supported by results obtained following administration of the 5-lipoxygenase inhibitors ONO-LP-016 and AA-861 [22].
• This study was performed to examine the effects of a 5-lipoxygenase inhibitor (AA-861), a selective leukotriene receptor antagonist (ONO-1078), and a cyclooxygenase inhibitor (indomethacin) on endotoxin-induced mortality and TNF production in mice [4].
• The effect of a selective thromboxane synthetase inhibitor, OKY-046, and a selective 5-lipoxygenase inhibitor, AA-861, on bronchial responsiveness to acetylcholine was studied in 23 asthmatic subjects [12].
• A single oral dose of a selective 5-lipoxygenase inhibitor (AA-861, 80 mg.kg-1, 1 h before ligation) lowered the leukotriene B4 concentration to that of the sham operated hearts and decreased the leucocyte count by 49.4% and 41.2% at 12 and 24 h respectively [23].
• These findings suggest that AA-861 reduced liver allograft rejection by suppressing the elevation of 5-lipoxygenase products and increasing PGE2 production in the early stage of rejection [8].

Gene context of DOCEBENONE

• These results indicate that AA-861 selectively inhibits 5-lipoxygenase but not cyclooxygenase or 12-lipoxygenase in human specimens [24].
• The SEB-induced neutrophil accumulation in BAL fluid was reduced by pretreatment with dexamethasone (0.5 mg/kg), the COX-2 inhibitor celecoxib (3 mg/kg), the selective iNOS inhibitor compound 1400 W (5 mg/kg) and the lipoxygenase inhibitor AA-861 (200 mug/kg) [25].
• The ratio cyclooxygenase/lipoxygenase products increased with AA-861 but not with NDGA [26].
• AA-861 also significantly prevented the formation of intestinal ulcers induced by Indo [27].
• 5. Indomethacin (a cyclo-oxygenase inhibitor), AA-861 (a selective 5-lipoxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist), methysergide (a 5-hydroxytryptamine D-receptor antagonist) and pyrilamine (a histamine H1-receptor antagonist) exerted little or no effect on PLA2-induced AH to cooling [28].

Analytical, diagnostic and therapeutic context of DOCEBENONE

• No significant differences were observed in regional CBF in the AA-861- and vehicle-pretreated gerbils during reperfusion [9].
• The animals were divided into three groups: control group; administered AA-861 in a single dose of 30 mg/kg; and administered AA-861 in a single dose of 60 mg/kg [29].
• Premedication with AA-861, a lipoxygenase inhibitor, decreased dose-dependently peptide LT contents 1 hr after HCl administration [30].
• An analysis of the anaphylactic diffusate from the human lung fragments, using the combined technique of high performance liquid chromatography and radioimmunoassay, revealed that AA-861 markedly suppresses biosynthesis of the leukotrienes [10].

References