Inhibition of leukotriene biosynthesis in the rat peritoneal cavity

Young, Patrick; Bell, Randy L.; Lanni, Carmine; Summers, James Bradley; Brooks, Dee W.; Carter, George W.

doi:10.1016/0014-2999(91)90907-8

Cited by 31 publications

(22 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These include poor penetration into the peptidoleukotriene-producing tissues (such as the lung parenchyma, liver and kidney) [48,49,50], or loss of potency in the intercellular protein-rich environment of these organs. A similar result in rodents with zileuton (4-fold shift in ED 50 for inhibition of peritoneal LTB4 production compared with whole blood) has recently been reported [54]. In contrast, the hydrophobic nature of the FLAPbinding indoles, MK-886 and MK-0591, may partially account fo their enhanced ability to inhibit in vivo LT synthesis compared with blood LTB 4.…”

Section: Discussionsupporting

confidence: 58%

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Tagari¹,

Brideau²,

Chan³

et al. 1993

Agents and Actions

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 58%

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Tagari¹,

Brideau²,

Chan³

et al. 1993

Agents and Actions

View full text Add to dashboard Cite

show abstract

“…We have got evidence that LTs and PGs are mainly involved in AA (0.25 mg)-induced ear edema in mice (25). In the present study, AL-3264 suppressed the AA-induced ear edema at oral doses over 40 mg/kg as well as zileuton, which was chosen as a reference drug because its potent oral activity is superior to that of AA-861 (26). AL-3264 has no inhibi tory effect on carrageenan-induced edema in rat hind paw at an oral dose of 80 mg/kg (K. Ishii, unpublished obser vation), suggesting that AL-3264 does not inhibit CO activity.…”

Section: Discussionmentioning

confidence: 65%

Inhibition of Leukotriene Production by N-(4-(4-(Diphenylmethyl)-1-piperazinyl)butyl)-3-(6-methyl-3-pyridyl) Acrylamide (AL-3264), a New Antiallergic Agent.

et al. 1994

View full text Add to dashboard Cite

ABSTRACT-The effects of AL-3264, which exhibits a 5-lipoxygenase (5-LO) inhibiting property by block ing histamine H1-receptors and inhibition of histamine release, were examined on leukotriene (LT) pro duction and LT-mediated responses. AL-3264 (1 30 tiM) inhibited the A23,187-induced LT production from human leukocytes with almost the same potency as that of nordihydroguaiaretic acid. AL-3264 (30 100 mg/kg, p.o.) inhibited the antigen-induced LT production in the abdominal cavity of passively sen sitized rats; its effect was as potent as that of AA-861, a 5-LO inhibitor. AL-3264 (30,uM) suppressed both the initial and sustained phases of the antigen-induced contractions in isolated trachea from actively sensi tized guinea pig. Phenidone (3 1M), a dual inhibitor of 5-LO and cyclooxygenase (CO), suppressed the sus tained phase, while indomethacin was without effect on either phase. AL-3264 (40-160 mg/kg, p.o.) sup pressed the arachidonic acid-induced ear edema in mice, for which 5-LO inhibitors were effective but antihistamines were not. The anti-edematous effect of AL-3264 (160 mg/kg) was reduced by intradermal ad ministration of LTC4 (0.1 pg). These results suggest that AL-3264 suppresses LT production in vivo and in vitro by inhibiting 5-LO activity, and this property may contribute to the antiallergic effect of AL-3264.

show abstract

“…The development of new agents capable of interfering with the synthesis or action of these potent substances may help to more fully explore this issue. Lipoxygenase synthesis inhibitors (1,4,5,8,16,31,37,38,42,58,60) and leukotriene receptor antagonists (17,20,29,31,36,38) have been shown to inhibit the action of leukotrienes and/or HPETE and HETE acids. In a few cases, this therapeutic strategy has shown some potential to prevent the development of delayed cerebral vasospasm after experimental SAH (20,49,58).…”

Section: Discussionmentioning

confidence: 99%

The Novel 5-Lipoxygenase Inhibitor ABT-761 Attenuates Cerebral Vasospasm in a Rabbit Model of Subarachnoid Hemorrhage

et al. 2001

View full text Add to dashboard Cite

show abstract

Inhibition of leukotriene biosynthesis in the rat peritoneal cavity

Cited by 31 publications

References 21 publications

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Inhibition of Leukotriene Production by N-(4-(4-(Diphenylmethyl)-1-piperazinyl)butyl)-3-(6-methyl-3-pyridyl) Acrylamide (AL-3264), a New Antiallergic Agent.

The Novel 5-Lipoxygenase Inhibitor ABT-761 Attenuates Cerebral Vasospasm in a Rabbit Model of Subarachnoid Hemorrhage

Contact Info

Product

Resources

About