New developments concerning leukotriene antagonists: a review

Musser, John H.; Kreft, Anthony F.; Lewis, Alan J.

doi:10.1007/bf01964994

Cited by 18 publications

(9 citation statements)

References 50 publications

(46 reference statements)

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“…in this model of LT-mediated allergic bronchospasm. FPL-55712 and LY-171,883 are considered to be equipotent antagonists of LTD,, although LY-171,883 has oral activity [24]. This has been confirmed here against a LT-mediated allergic bronchospasm.…”

Section: Discussionsupporting

confidence: 55%

“…In addition, soybean trypsin inhibitor was inactive thus minimizing a role for kinins that may be formed by anaphylactic lung [63,64]. Most importantly, the bronchospasm was inhibited by the selective LTD,~ antagonists FPL-55712 [23], LY-171,883 [24] and ICI-198,615 [25]. 615 was the most potent of the receptor antagonists.…”

Section: Discussionmentioning

confidence: 99%

“…Regardless of the vehicle or route of administration, control bronchospasms were generally a 250-350% increase of tung inflation above baseline. Table 1 indicates that the selective LT antagonists FPL-55712 [23], LY-171,883 [24] and ICI-198,615 [25] inhibited the LT-mediated allergic broncho- (Table 1). Compounds reported to inhibit 5-1ipoxygenase activity and LT-biosynthesis in vitro were not uniformly active against a LT-mediated, allergic bronchospasm (Table 2).…”

Section: Development Of Bronchospasm Modelmentioning

confidence: 99%

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The effect of leukotriene antagonists, lipoxygenase inhibitors and selected standards on leukotriene-mediated allergic bronchospasm in guinea pigs

Kreutner¹,

Sherwood²,

Rizzo³

1989

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Leukotrienes (LT) C4, D4, and E4 are major contributors to the pathobiology of human bronchial asthma. Therefore, it is likely that compounds that antagonize the action or inhibit the formation of LTs will be useful therapeutic agents. We have studied the effects of LT antagonists, 5-lipoxygenase inhibitors and selected standards in a model of LT-mediated allergic bronchospasm in guinea pigs. Sensitized animals were pretreated with mepyramine, indomethacin and propranolol to eliminate the influence of histamine, prostaglandins, thromboxanes and circulating catecholamines. In these animals, inhalation of antigen resulted in a bronchospasm consistent with a LT-mediated response that was slow in onset, of long duration and was inhibited by the selective LTD4, antagonists FPL-55712, LY-171,883 and ICI-198,615. ICI-198,615 was approximately 50-times more potent than FPL-55712 by the intravenous and intratracheal routes. However, of thirteen compounds known to inhibit 5-lipoxygenase and LT biosynthesis in vitro only phenidone, piriprost and AA-861 were active in this in vivo model. The allergic bronchospasm was inhibited by bronchodilators (e.g. PGE2, aminophylline and forskolin) and by some mast cell stabilizers, but was otherwise insensitive to other pharmacological classes of compounds including calcium channel blockers and antagonists of serotonin, acetylcholine and platelet-activating factor. This model seems useful and reasonably selective for the evaluation of new antianaphylactic compounds that are LT antagonists. The inactivity of many 5-lipoxygenase inhibitors in this model suggests they do not inhibit LT formation in vivo.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Development Of Bronchospasm Modelmentioning

confidence: 99%

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The effect of leukotriene antagonists, lipoxygenase inhibitors and selected standards on leukotriene-mediated allergic bronchospasm in guinea pigs

Kreutner¹,

Sherwood²,

Rizzo³

1989

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“…Separate receptor sites have been identified both for LTC4 and for LTD4 and these sites are distinguished by either radioligand receptor binding or differing responses to antagonists (see Bruns et al, 1983;Mong et al, 1984;Cheng et al, 1985;Musser, Kreft & Lewis, 1986;Sarau et al, 1987;Tamura, Agrawal & Townley, 1987). A LTD4 receptor seems also to be present in the plasma membrane of the Ehrlich ascites cells since the LTD4-induced acceleration of RVD is almost abolished in the presence of the LTD4 receptor antagonist L-649,923 (Fig.…”

Section: Receptor-mediated Effect Of Ltd4 On the Separate K And C1 Trmentioning

confidence: 99%

Leukotriene-D4 induced cell shrinkage in Ehrlich ascites tumor cells

Lambert

1989

J. Membrain Biol.

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The nature of the leukotriene-D4 (LTD4) induced cell shrinkage in Ehrlich ascites tumor cells has been investigated. LTD4 treatment of Ehrlich cells induces net loss of cellular KCl and cell shrinkage independent of the initial cell volume. LTD4 also produces water loss and reduction in cell volume when all extracellular and all intracellular Cl has been replaced by NO3. On the other hand, LTD4 fails to produce any significant changes in cell volume in the presence of the K-channel blocker quinine, suggesting that LTD4 in Ehrlich cells induces Cl-independent K loss through the Ca2+-dependent K channels. However, the effect of physiological doses of LTD4 on cell volume seems not to be as potent in Cl-free, NO3 cells when compared to Cl-containing cells, indicating that LTD4 in Ehrlich cells also provokes Cl-dependent K loss. LTD4 seems not to produce K loss through an electroneutral K+/H+ exchange system. LTD4 still produces Cl-independent K loss and cell shrinkage in the presence of the anti-calmodulin drug pimozide but not in the presence of the LTD4 receptor antagonist L-649,923 or the 5-lipoxygenase inhibitor NDGA. Pretreatment of the cells with pertussis toxin, which inactivates inhibitory guanine nucleotide binding proteins (G-proteins), leads to partial inhibition of the LTD4-induced shrinkage. It is suggested that the LTD4-induced activation of K and Cl transporting systems in Ehrlich ascites tumor cells is mediated via a G-protein coupled receptor and that LTD4 might exert its effect through another lipoxygenase product. The Ca2+-calmodulin complex is not involved in the LTD4-induced activation of K and Cl transporting systems.

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“…Receptor blockade is regarded as a promising approach to antagonize leukotriene action. A variety of potent leukotriene receptor antagonists have been designed (Musser et al, 1986;Snyder & Fleisch, 1989). There is no doubt that many leukotriene effects are mediated via receptors (Crooke et al, 1989;Halushka et al, 1989), but it is not known to date whether leukotriene inactivation also proceeds via receptormediated events.…”

Section: Introductionmentioning

confidence: 99%

Effect of the leukotriene receptor antagonists FPL 55712, LY 163443, and MK‐571 on the elimination of cysteinyl leukotrienes in the rat

Denzlinger

Grimberg

Kapp

et al. 1991

British J Pharmacology

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Leukotriene elimination via bile and urine is an important mechanism of inactivation for these potent lipid mediators. We investigated whether the elimination of cysteinyl leukotrienes is a target for the action of leukotriene receptor antagonists. Experiments were performed in male rats under deep thiopentone anaesthesia. The bile duct and the urinary bladder were cannulated. Tritium labelled leukotrienes and leukotriene receptor antagonists were given via central venous catheters. Elimination of leukotrienes produced in vivo was studied following stimulation of endogenous leukotriene biosynthesis by operative trauma. 3H‐leukotriene metabolites were identified by h.p.l.c. analysis. Leukotrienes produced in vivo were measured by combined use of h.p.l.c. and RIA. Under control conditions, 49 ± 12% of the injected 3H‐leukotriene radioactivity was recovered in bile and 1 ± 0.8% in urine within 90 min. Operative trauma resulted in initial hepatobiliary secretion of 887 ± 206 pmol kg−1 h−1 of the endogenous leukotriene metabolite N‐acetyl leukotriene E4 (LTE4NAc). FPL 55712 strongly inhibited hepatobiliary elimination of 3H‐leukotriene radioactivity in a dose‐dependent manner after i.v. injection of [3H]‐LTC4, [3H]‐LTD4 or [3H]‐LTE4, respectively. Biliary [3H]‐LTD4 was reduced most effectively. The leukotriene antagonist potently prevented biliary elimination of LTE4NAc produced in vivo. Bile flow and elimination from blood into bile of [3H]‐ouabain were also impaired by FPL 55712, but to a lesser extent. LY 163443 reduced biliary [3H]‐LTD4 after i.v. administration of [3H]‐LTD4. However, the total elimination of 3H‐leukotriene metabolites into bile was not significantly inhibited by the drug. MK‐571 reduced the biliary concentration of tracer after administration of 3H‐leukotrienes most potently with respect to [3H]‐LTD4. In contrast, the total recovery of 3H‐leukotrienes in bile tended to increase. This is explained by a drug‐induced increase in bile flow. Urinary elimination of 3H‐leukotrienes, quantitatively less important in the rat, was not significantly influenced by the leukotriene receptor antagonists. Recovery of 3H‐leukotriene radioactivity in liver and kidneys was quantitatively insignificant. From our data, we conclude that leukotriene receptor antagonists have the potential to affect leukotriene elimination by a mechanism not necessarily related to receptor blockade. Inhibition of elimination by the receptor antagonists may prolong the biological half life of leukotrienes. This effect may counteract the antagonistic properties of these drugs.

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New developments concerning leukotriene antagonists: a review

Cited by 18 publications

References 50 publications

The effect of leukotriene antagonists, lipoxygenase inhibitors and selected standards on leukotriene-mediated allergic bronchospasm in guinea pigs

The effect of leukotriene antagonists, lipoxygenase inhibitors and selected standards on leukotriene-mediated allergic bronchospasm in guinea pigs

Leukotriene-D4 induced cell shrinkage in Ehrlich ascites tumor cells

Effect of the leukotriene receptor antagonists FPL 55712, LY 163443, and MK‐571 on the elimination of cysteinyl leukotrienes in the rat

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