Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20292 (FLAP)
 563 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In man, the therapeutic effectiveness of specific inhibitors of leukotriene (LT) biosynthesis against allergen-induced bronchoconstriction appears to be related to the in vivo biochemical efficacy of these compounds, as measured by inhibition of whole blood LTB4 generation (upon A23187 stimulus) and, particularly, urinary LTE4 excretion. Accordingly, we have assessed the ability of two clinically documented LT biosynthesis inhibitors, zileuton and MK-886, and the structurally novel 5-lipoxygenase activating protein antagonist, MK-0591, to inhibit the production of these inflammatory arachidonic acid metabolites in laboratory dogs. Zileuton (2 mg/kg) was extremely bioavailable in dogs (> 10 microM plasma concentrations), and inhibited the A23187-induced ex vivo production of LTB4 by venous blood by > 90%, in concordance with its potency in canine blood in vitro (IC50 = 1.1 microM). Despite this degree of inhibition in whole blood, urinary LTE4 excretion was reduced by only 52%, a profile of activity similar to that seen in clinical studies. MK-886 was less well absorbed, with plasma concentrations of 3 microM being achieved only at 25 mg/kg. These levels resulted in < 45% inhibition of LTB4 production, but a significant (p < 0.05) 47% inhibition of urinary LTE4 excretion. MK-0591 was similarly bioavailable (compared with MK-886), but 10-fold more active in vivo as a 2 mg/kg dose resulted in 41-62% inhibition of urinary LTE4 excretion (p < 0.05 vs controls; n = 4, 28). Significant inhibition of ex vivo LTB4 synthesis was also observed at this dose (49%), in accord with peak plasma concentrations of 0.5 microM and an in vitro potency of 0.2-0.4 microM (IC50) in whole blood from these animals. At higher dose (10 mg/kg), MK-0591 inhibited LTE4 excretion by 69%, with 88% inhibition of the LT biosynthetic capacity of whole blood. These data demonstrate that the biochemical efficacy of structurally diverse leukotriene biosynthesis inhibitors can be assessed in vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful for predicting biochemical activity in man.
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PMID:Assessment of the in vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors. 814 71

In 16HBE transformed human bronchial epithelial cells, histamine stimulated interleukin (IL)-8 mRNA and protein secretion, and this histamine stimulation was inhibited by the H1-receptor antagonist diphenhydramine (DPH), by the inhibitor of 5-lipoxygenase-activating protein (FLAP) MK-886, by the 5-lipoxygenase inhibitor Zileuton, and by dexamethasone. Histamine stimulated bronchial epithelial cell production of leukotriene B4 (LTB4), and this production was inhibited by FLAP inhibitors MK-886 and L-655,238 and Zileuton. Histamine stimulated IL-8 luciferase reporter gene activity that was inhibited with DPH, dexamethasone, MK-886 and L-655,238, and Zileuton. The inhibition of IL-8 transcription and protein secretion by FLAP inhibitors and Zileuton was reversed with exogenous LTB4. There was increased IL-8 nuclear factor-kappaB (NF-kappaB) DNA-binding activity after histamine stimulation, and this was inhibited by DPH and MK-886. Cytoplasmic phospholipase A2 mRNA levels were also potently induced by histamine. Thus histamine stimulation of bronchial epithelial cells involves binding at H1 receptors, production of LTB4, activation of NF-kappaB and increased expression of IL-8.
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PMID:Leukotriene B4 mediates histamine induction of NF-kappaB and IL-8 in human bronchial epithelial cells. 960 43

Nordihydroguaiaretic acid (NDGA), an antioxidant and inhibitor of the lipoxygenase arm of the arachidonic acid metabolism, was recently demonstrated to inhibit transport of secretory proteins to the Golgi complex. We have investigated the effects of NDGA on the secretory and endocytic activity of cultured human blood dendritic cells (DC). Treatment with NDGA strongly diminished cytokine secretion by DC. Moreover, NDGA reduced in a dose- and time-dependent fashion fluid phase as well as receptor-mediated endocytosis in DC. Zileuton and MK-886, specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein, respectively, had no effect. Likewise, N-acetyl-L-cysteine, a thiol antioxidant precursor of glutathione, did not affect DC function. Finally, serum remarkably protected the cells from the inhibitory effects of NDGA. Our data demonstrate that NDGA not only disrupts vesicular transport along the secretory route but is also a potent inhibitor of the endocytic pathways in human DC and that NDGA has inhibitory properties different from those described.
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PMID:Nordihydroguaiaretic acid blocks secretory and endocytic pathways in human dendritic cells. 985 Jan 56

Leukotrienes are synthesized by different cells, including eosinophils, neutrophils, basophils, lymphocytes, macrophages, and mast cells. Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are the most important leukotrienes in the pathogenesis of asthma. Pharmacologically, there are two different ways of blocking the action of leukotrienes: inhibiting their production by blocking 5-lipoxygenase or its activating protein, 5-lipoxygenase-activating protein (FLAP), (inhibitors) or by blocking their receptors (antagonists). The available antagonists are, for the moment, directed against the one receptor demonstrated to play a role in asthma symptoms, CysLT1, and they act in a competitive way. The only marketed 5-lipoxygenase inhibitor is zileuton (Zyflo). CysLT1 antagonists, currently on the pharmaceutical market in some countries, are zafirlukast (Accolate), pranlukast (Ultair, Onon), and montelukast (Singulair). Undoubtedly, drugs acting on leukotrienes constitute a new pharmacologic class in the therapeutic armamentarium for the management of asthma. From the pediatric point of view, montelukast is currently the most interesting drug of the group to date because of published trials in patients as young as 6 yr of age. At present, zafirlukast is only approved for use in patients 12 yr of age and older, although we understand that applications are likely to extend the age range into childhood shortly. However, more experience is necessary to establish a definite place for both leukotrienes in the step-by-step asthma treatment. New comparative studies (with sodium cromoglycate and inhaled steroids), which will probably be published in the near future, as well as studies on the use of montelukast in the treatment of children under 6 yr of age will add crucial information to our knowledge, and help to identify an appropriate use in the therapeutic algorithm. Montelukast will not be a substitute for inhaled corticosteroids or beta-agonists, although it may act as a 'sparing drug' (which might help tapering of steroids in some instances). Its role in exercise-induced asthma seems promising. Although its more widespread use could highlight low-frequency adverse effects, its apparent excellent tolerability is an additional advantage for the drug. Patients' preference for a twice-daily dosage over the inhaled medication, resulting in a better compliance, is relatively well established, at least for zafirlukast in adults, and these findings can probably be extended to montelukast, which only requires once-daily dosing in children.
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PMID:New perspectives for asthma treatment: anti-leukotriene drugs. 1047 8

Thrombosis and inflammation involve complex platelet-leukocyte interaction, the details of which are not fully elucidated. Therefore, we investigated cross talk between platelets and leukocytes in whole blood, under the following physiological conditions: at 37 degrees C, with normal calcium concentrations, and with shear force. Platelet P-selectin and leukocyte CD11b expression were used to monitor platelet and leukocyte activation, respectively, and platelet-leukocyte aggregation (PLA) was analyzed. The leukocyte-specific agonist N:-formyl-methionyl-leucyl-phenylalanine (10(-6) mol/L) increased P-selectin-positive platelets from 2.5+/-0. 1% to 5.1+/-0.6% (P:<0.05). The increase was inhibited by either the platelet-activating factor (PAF) antagonist SR27417, the superoxide anion scavenger superoxide dismutase, the 5-lipoxygenase inhibitor Zileuton, or the 5-lipoxygenase-activating protein inhibitor MK-886, suggesting the involvement of PAF, superoxide anion, and 5-lipoxygenase products in leukocyte-induced platelet activation. The platelet-specific agonist collagen (1 microg/mL) increased leukocyte CD11b expression from 2.94+/-0.52 to 3.81+/-0.58 (P:<0. 05); this was not inhibited by the thromboxane A(2) receptor antagonist ICI 192.605 or the PAF antagonist SR27417. Platelet P-selectin expression induced by N:-formyl-methionyl-leucyl-phenylalanine and leukocyte CD11b expression induced by collagen could be suppressed by glycoprotein IIb/IIIa blockade or P-selectin blockade. This study documents platelet-leukocyte cross talk under conditions that mimic a physiological state and suggests that this involves multiple mediators and mechanisms. Furthermore, new evidence of integrin and selectin involvement in intracellular and intercellular signaling during platelet-leukocyte cross talk is provided.
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PMID:Platelet-leukocyte cross talk in whole blood. 1111 75