[Montelukast]

[Article in German]

Eschenhagen T.

Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Germany.

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The action of cysteinyl-leukotrienes on intracellular calcium mobilization in human detrusor myocytes.

Hald T.

Department of Urology, Herlev Hospital, University of Copenhagen, Denmark.

OBJECTIVE: To investigate the presence of leukotriene D4 receptors in fura-2-loaded human detrusor smooth muscle cells (DSMCs) by examining the ability of leukotriene D4 to raise intracellular-free Ca2+ concentration ([Ca2+]i), to determine the origin of the leukotriene D4-mediated rise in [Ca2+]i and to investigate whether the specific leukotriene D4 receptor antagonist montelukast inhibits the Ca2+ response induced by leukotriene D4. MATERIALS AND METHODS: Detrusor muscle biopsies were obtained from patients with benign noninvasive bladder diseases undergoing cystoscopy. DSMCs were isolated using an explant technique and maintained in culture. Only primary cultures or cells passaged up to three times were used for experiments. DSMCs were characterized with immunohistochemical staining and their identity confirmed by transmission electron microscopy. [Ca2+]i was measured in single DSMCs using the Ca2+ probe fura-2 and fluorescence-ratio microscopy. RESULTS: Immunohistochemical staining showed that 80-99% of the cells were positive for smooth muscle alpha-actin. The ultrastructural features of the cultured cells were those of smooth muscle cells and showed no differentiation in a fibroblastic or myofibroblastic direction. Leukotriene D4 increased the level of [Ca2+]i in a dose-dependent manner. Calcium was mobilized almost exclusively from intracellular Ca2+ stores. There was a dose-dependent inhibition of the increase in [Ca2+]i by montelukast. CONCLUSION: The present study is the first to show the presence of specific leukotriene D4 receptors in human detrusor myocytes. This may have implications for a potential pathophysiological role of leukotriene D4 in patients with interstitial cystitis and other functional or inflammatory bladder disorders.

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Leukotriene antagonism reduces the generation of endothelin-1 and interferon-gamma and inhibits eosinophilic airway inflammation.

Skjonsberg OH.

Department of Pulmonary Medicine, Ulleval Hospital, University of Oslo, Norway. finn finsnes.no

The cysteinyl leukotrienes (cysLTs) and the peptide hormone endothelin (ET)-1 are potent bronchoconstrictor substances, and these mediators are also claimed to be implicated in the development of eosinophilic airway inflammation. In the present study, we have investigated the effect of the cysLT1 receptor antagonist montelukaston the development of an eosinophilic airway inflammation 24 h after intratracheal Sephadex (SDX) provocation in rats. Furthermore, the effect of montelukast treatment on the generation of ET-1 and other pro-inflammatory mediators has been studied. The inflammatory response was significantly reduced in the animals receiving SDX + montelukast compared to animals receiving solely SDX, as evaluated by a decrease in bronchoalveolar lavage fluid total cell count (10.3 +/- 1.2 vs. 18.5 +/- 1.8 x 10(4) ml(-1), P<0.001), number of eosinophils (299.7 +/- 43.8 vs. 577.6 +/- 46.6 x 10(2) ml(-1), P<0.001), and lymphocytes (116.8 +/- 20 vs. 222.0 +/- 34.8 x 10(2) ml(-1), P<0.05), as well as the degree of tissue inflammation (P<0.05). Montelukast also inhibited the increase in the concentration of the pro-inflammatory mediators ET-1 (28.5 +/- 75 vs. 40.9 +/- 7.3 x pg ml(-1), P<0.05) and interferon (IFN)-gamma (4.3 +/- 2.2 vs. 15.6+/-8.7 x pg ml(-1), P<0.05), but not tumor necrosis factor-gamma or interleukin-8. In summary, treatment with the cysLT1 receptor antagonist montelukast reduced the inflammatory response during development of an eosinophilic airway inflammation, possibly by inhibiting the release of pro-inflammatory mediators like ET-1 and IFN-gamma.

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Variability and lack of predictive ability of asthma end-points in clinical trials.

Reiss TF.

Dept of Clinical Biostatistics and Clinical Research, Merck Research Laboratories, Rahway, NJ 07665, USA.

While a consensus definition of the clinical parameters important in asthma control exists, an adequate objective definition of a response to asthma treatment and parameters for prediction of that response remain undefined. Given that asthma is a complex biological disease and that different parameters may measure dissimilar aspects of the disease status, this study assessed the relationship among several end-points of asthma control, and attempted to select a combination of variables measured before (baseline characteristics) or early in asthma therapy which would be predictive of a long-term clinical response. Data from two previously reported clinical studies which included montelukast, inhaled beclomethasone, and placebo in mild-to-moderate asthmatics (n=1,576) were analysed. The forced expiratory volume in one second (FEV1), daily symptoms score (DSS), beta-agonist use, and morning peak expiratory flow (PEFAM) were recorded during the baseline period and throughout the 12-week treatment period. For the long-term response, as measured during the last 9 weeks of treatment, there was a large within-patient variability and no more than a moderate correlation between the changes in FEV1 and PEFAM; DSS and FEV1; and DSS and beta-agonist use. The overall predictive values for FEV1 and DSS were 70-80%. The results showed that multiple measurements over a length of time are needed to establish a more complete profile of response, and that demographic and early treatment responses had a small but inadequate ability to predict future response. This study demonstrates the complex relationship among asthma end-points and the difficulty of reliably estimating long-term response using common, surrogate clinical markers of asthma control.

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Lateral membrane LXA4 receptors mediate LXA4's anti-inflammatory actions on intestinal epithelium.

Williams IR.

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA.

Lipoxin A(4) (LXA(4)) and its stable analogs downregulate chemokine secretion in polarized epithelia. This anti-inflammatory effect has been suggested to be mediated by the LXA(4) receptor (LXA(4)R), a G protein-coupled receptor. To determine whether LXA(4)R is expressed on the apical, basolateral, or both poles of intestinal epithelia, an NH(2)-terminal c-myc epitope tag was added to the human LXA(4)R cDNA and recombinant retroviruses were used to transduce polarized epithelial cells. In polarized T84 intestinal epithelial cells, c-myc-LXA(4)R was preferentially expressed on the basolateral surface as indicated by cell surface-selective biotinylation and confocal microscopy. Furthermore, expression of c-myc-LXA(4)R and a truncation mutant lacking the cytoplasmic terminus was primarily confined to the lateral subdomain. We also observed that the expression of myc-LXA(4) conferred enhanced downregulation of IL-8 expression in response to LXA(4) analog and that blockade of the CysLT1 receptor by montelukast did not prevent this response to LXA(4) analog. Thus LXA(4) generated in or near the paracellular space via neutrophil-epithelial interactions can rapidly act on epithelial LXA(4)R to downregulate epithelial promotion of intestinal inflammation.

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