FPL 55712

Attenuation of ozone-induced airway permeability in rats by pretreatment with cyclophosphamide, FPL 55712, and indomethacin.[Pubmed:1320904]

Am J Respir Cell Mol Biol. 1992 Jul;7(1):73-80.

Exposure of rats to ozone (O3) produces an increase in airway permeability and a concomitant influx of polymorphonuclear leukocytes in the lung. These observations raise the possibility that the inflammatory cells play a role in the cellular injury and increased airway permeability after O3 exposure. This study was therefore designed to determine if the inflammatory cells or their products are essential for the O3 effect. In a series of experiments, rats were rendered leukopenic with cyclophosphamide, treated with leukotriene B4 (LTB4), or with the inhibitors of lipoxygenase or cyclooxygenase products of arachidonic acid, followed by exposure to O3. A 2-h exposure to 0.8 ppm O3 caused a significant increase in the flux of proteins and albumin in bronchoalveolar lavage (BAL) and elevated the transport of 99mTc-diethylenetriaminepentaacetate (99mTc-DTPA) from trachea to blood. The treatment with cyclophosphamide caused a significant reduction in the circulating and pulmonary leukocytes and prevented an increase in tracheal mucosal permeability to 99mTc-DTPA and the protein and albumin flux in BAL. While the intratracheal instillation of LTB4 did not affect the permeability, tracheal permeability and albumin levels in BAL in rats treated with LTD4 antagonist FPL 55712 and exposed to O3 were lower than in the untreated O3-exposed rats. Pretreatment with indomethacin also prevented the O3 effects, as reflected by the decreased protein and albumin flux in BAL and 99mTc-DTPA transport from trachea to blood. These data show a reduction in the effect of O3 by agents that affect leukocytes or their products. The results support a mechanism of increased permeability that is dependent upon inflammatory cells and their products.

MCI-826 is a potent and selective antagonist of peptide leukotrienes (p-LTs) and has characteristics distinctive from those of FPL 55712.[Pubmed:1460800]

Jpn J Pharmacol. 1992 Sep;60(1):1-8.

Antagonistic effects of a newly synthesized compound, (E)-2,2-diethyl-3'-[2-[2-(4-isopropyl)thiazolyl]ethenyl]succinanilic+ ++ acid sodium salt (MCI-826) on the contraction of the isolated guinea pig trachea and human bronchus induced by various agonists including peptide leukotrienes (p-LTs), histamine, acetylcholine (ACh), prostaglandin (PG) D2 and others were investigated and compared with the effects of a p-LT antagonist, FPL 55712, in some experiments. MCI-826 potently antagonized LTD4- and LTE4-induced contractions at extremely low concentrations in the isolated guinea pig trachea with pA2 values of 8.3 and 8.9, respectively, on a molar basis. These values indicated that MCI-826 is over 100 times stronger than FPL 55712. Similarly, MCI-826 at 10(-8) g/ml (2.4 x 10(-8) M) markedly antagonized LTD4-induced contractions of the isolated human bronchus. Although FPL 55712 fairly inhibited the 10(-9) g/ml LTC4-induced contraction of the isolated guinea pig trachea, MCI-826 had little effect on the contraction at high concentrations like 3 x 10(-6) g/ml (7.1 x 10(-6) M). MCI-826 modestly affected the other agonist-induced contractions and the resting tonus of the isolated guinea pig trachea at 10(-6) g/ml (2.4 x 10(-6) M) or higher concentrations, but FPL 55712 caused fair inhibition of some of those contractions and gradually lowered the resting tonus with time. These results indicate that MCI-826 is a highly potent and selective antagonist of LTD4 and LTE4 and can be a useful tool for biological and pharmacological experiments on p-LTs.

Effect of the leukotriene receptor antagonists FPL 55712, LY 163443, and MK-571 on the elimination of cysteinyl leukotrienes in the rat.[Pubmed:1855116]

Br J Pharmacol. 1991 Apr;102(4):865-70.

1. 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. 2. 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. 3. 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). 4. 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. 5. 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. 6. 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. 7. 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. 8. 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.

Leukotrienes mediate tracheal hyperresponsiveness after nitric oxide synthesis inhibition.[Pubmed:8566126]

Eur J Pharmacol. 1995 Oct 16;285(2):R1-2.

Preincubation of guinea pig tracheas with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 120 microM) resulted in a significant upward shift of the histamine concentration-response curve with a concomitant inhibition of prostaglandin E2 production. Preincubation of the preparations with a 5-lipoxygenase inhibitor (AA-861, 2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-p-benzoquinone) or a leukotriene C4,D4,E4 receptor antagonist (FPL 55712, sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy propoxy]-4-oxo-8- propyl-4H-1-benzopyran-2-carboxylate) totally blocked the L-NAME-induced tracheal hyperresponsiveness. A shift from cyclo-oxygenase to lipoxygenase products, in particular leukotrienes, is likely to be responsible for the L-NAME-induced tracheal hyperresponsiveness.

Pharmacologic properties of FPL 55712 administered by aerosol.[Pubmed:6322547]

Agents Actions. 1984 Jan;14(1):43-8.

FPL 55712 was investigated by the aerosol route of administration for efficacy at protecting against leukotriene-induced bronchoconstrictions in guinea pigs and for mediator release inhibitory activity in passively sensitized rats. In the studies to investigate leukotriene antagonism; anesthetized, spontaneously breathing guinea pigs were pretreated with propranolol and were exposed via tracheal cannula to aerosols generated by a Monaghan nebulizer. Subsequently, the animals were artificially ventilated and challenged with LTD4 or LTE4 (25 micrograms/kg, i.v.). FPL 55712 produced a concentration-dependent inhibition of LTD4 and LTE4-induced bronchoconstriction (IC50's 0.5% and 0.8%, respectively). Although the biologic half-life of FPL 55712, administered intravenously, was very short (1.7 minutes against LTD4 and 1.2 minutes against LTE4) after aerosol administration the biological half-life was surprisingly long (120 minutes against LTD4 and 90 minutes against LTE4). Aerosolized FPL 55712 also possessed weak antiallergic activity in comparison to disodium cromoglycate when measured as an inhibitor of IgE-mediated anaphylactic bronchoconstriction in rats (IC50's of 2.0% and 0.01%, respectively). Thus, these studies demonstrate that, when administered by aerosol, FPL 55712 is effective at protecting against leukotriene-induced bronchoconstrictions, exhibits a long duration of action and also possesses weak antiallergic activity.

Pharmacological study of the effects of leukotrienes C4, D4, E4 & F4 on guinea pig trachealis: interaction with FPL-55712.[Pubmed:6322240]

Prostaglandins. 1983 Nov;26(5):833-43.

Leukotrienes D4 greater than C4 greater than E4 greater than F4 produced qualitatively similar contractions of guinea-pig trachealis, which were antagonized by the SRS-antagonist FPL-55712. Schild analyses indicated that FPL-55712 when tested in a low concentration range (0.57 - 5.7 X 10(-6) M) was a competitive antagonist of LTC4, LTE4 and LTF4 (slope not significantly different from one). The interaction of FPL-55712 with LTD4 may be noncompetitive (slope less than 1). Comparison of the calculated dissociation constants (-log KB) indicated that FPL-55712 was more effective at blocking LTE4 and LTF4 compared to LTC4 and LTD4. In the presence of higher concentrations of FPL-55712 (1.9 X 10(-5) M) the antagonism of LTC4 became noncompetitive. These findings indicate that important differences exist in the interaction of FPL-55712 with the various peptido leukotrienes in guinea pig trachealis. Discovery of more selective antagonists will be needed to determine if multiple receptor subtypes are present in this tissue.