The ACh-induced contraction in rat aortas is mediated by the Cys Lt1 receptor via intracellular calcium mobilization in smooth muscle cells.

Failli P.

Department of Pharmacology, University of Florence, Viale Pieraccini, 6 50139 Florence, Italy.

1. Our previously published data indicate that an endogenously produced 5-lipoxygenase metabolite can strongly contract isolated endothelium-preserved rat aortic strips when cyclo-oxygenase isoenzymes are inhibited. Therefore, we decided to investigate if cysteinyl-containing leukotrienes (Cys Lts) are involved in this endothelium-dependent contraction. 2. The isometric contraction of endothelium-preserved rat aortic strips was recorded in preparations preincubated with 5 microM indomethacin and precontracted with phenylephrine, adjusting resting tension at 0.7 g. Acetylcholine (ACh) contracted control strips. Montelukast and MK-571, selective type 1 Cys Lts receptor (Cys Lt(1)) antagonists and the Cys Lt(1)/Cys Lt(2) (type 2 Cys Lts receptor) antagonist BAYu9773 dose-dependently prevented ACh-induced contraction, their IC(50)s being 2.2, 3.1 and 7.9 nM respectively. The leukotriene B4 receptor antagonist U75302 was far less potent (IC(50) 1.5 microM). 3. In rat aorta smooth muscle cells (RASMs), Western blot analysis showed the presence of Cys Lt(1) and Cys Lt(2) receptors, the Cys Lt(1) receptor being predominantly expressed. 4. In fura-2 loaded RASMs, LTD4 (0.01-100 nM) and LTC4 (200-800 nM) dose-dependently increased intracellular calcium concentration ([Ca(2+)](i)). Montelukast (1-100 nM) reduced LTD4-induced [Ca(2+)](i) increase, its IC(50) being approximately 10 nM. BAY u9773 exhibited significantly low effectiveness. 5. LTD4 (10 nM) induced a redistribution of smooth muscle actin fibres throughout the cytoplasm as visualized by confocal microscopy. 6. In conclusion, Cys Lt(1) activation by endogenously produced Cys Lts, can contract rat aortas, while Cys Lt(2) only marginally influences aortic tone. Intracellularly, this effect is mediated by an increase in [Ca(2+)](i). Therefore, Cys Lts, by inducing vascular contraction, can contribute to systemic hypertension.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12598425&dopt=Abstract montelukast, Singulair




Simultaneous determination of montelukast and loratadine by HPLC and derivative spectrophotometric methods.

Satyanarayana A.

Department of Physical Chemistry, School of Chemistry, Andhra University, Visakhapatnam 530 003, AP, India.

In this study, high performance liquid chromatography (HPLC) and second derivative spectrophotometry have been used and described for the simultaneous determination of montelukast and loratadine in pharmaceutical formulations. HPLC separation was achieved with a Symmetry C18 column and sodium phosphate buffer (pH adjusted to 3.7): acetonitrile (20:80, v/v) as eluent, at a flow rate of 1.0 ml/min. UV detection was performed at 225 nm. The LC method is simple, rapid, selective and stability indicating for the determination of montelukast. 5-Methyl 2-nitrophenol was used as internal standard for the purpose of quantification of both the drugs in HPLC. In the second-order derivative spectrophotometry, for the determination of loratadine the zero-crossing technique was applied at 276.1 nm, but for montelukast peak amplitude at 359.7 nm (tangent method) was used. Both methods were fully validated and a comparison was made for assay determination of selected drugs in formulations. The results confirm that the methods are highly suitable for its intended purpose.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12609675&dopt=Abstract montelukast, Singulair




Anti-inflammatory effects of high-dose montelukast in an animal model of acute asthma.

Li W.

Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China. adrianwu hku.hk

BACKGROUND: Asthmatic inflammation is mediated by a network of cytokines, chemokines and adhesion molecules. Corticosteroids are the only effective agents available to control asthmatic inflammation. We investigated the effect of high-dose montelukast (MK), a selective cysteinyl leukotriene receptor 1 antagonist, on mediators of airway inflammation. OBJECTIVE: The aim of this study was to determine the effect of a 3-day course of high-dose MK on mediators of airway inflammation induced by a single allergen challenge in sensitized mice. METHODS: Ovalbumin (OVA)-sensitized BALB/c mice were treated with 25 mg/kg of MK or saline intravenously for 3 days. On the third day, a single inhalation challenge with OVA was given. Cellular infiltration was assessed in the bronchoalveolar lavage (BAL) and in the lung. Expression of IL-4, IL-5, IL-13 and eotaxin in the BAL, and the lung was determined. Serum IL-5 and total IgE was measured. IL-5 and eotaxin mRNA expression in the lung was determined. Finally, eotaxin and VACM-1 expression in the lung was assessed by immunohistochemistry. RESULTS: MK reduced the number of eosinophils in the BAL by > 90%. There was also significant reduction in IL-5 in the BAL, lung and the serum, and IL-5 mRNA expression in the lung. IL-4 level in the lung and BAL, and IL-13 level in the lung also significantly decreased. Serum IgE level and lung VCAM-1 expression was also significantly lower in treated animals, but eotaxin protein and mRNA expression in the lung remained unchanged. CONCLUSION: MK exerts its anti-inflammatory effect through the suppression of T helper type-2 (Th2) cytokines. The use of high-dose MK as an anti-inflammatory agent in acute asthma should be further explored.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12614451&dopt=Abstract montelukast, Singulair




Anti-leukotriene drugs in the prevention and treatment of hepatorenal syndrome.

Capella GL.

Via Sauli 7, Milan 20127, Italy. progderm katamail.com

Hepatorenal syndrome (HRS) is a peculiar form of progressive renal failure complicating the course of cirrhosis and ascites. The renal impairment of HRS is merely functional and potentially reversible. Notwithstanding, in spite of several encouraging attempts, a satisfactory medical treatment for HRS is still expected. Several pathophysiological mechanisms are active in HRS. Arachidonate metabolism derangements are among these, and prostaglandins and thromboxane antagonists have been tried with variable outcomes. Also leukotrienes (LT) appear to be involved in HRS. Three drugs (zileuton, montelukast and zafirlukast) interfering with LT synthesis and receptor binding are currently available, but they have not yet been tried in HRS. Accordingly, the author would like to suggest physicians engaged in care of these critical patients to consider a trial with these drugs-as well as with any future innovative agent active on the arachidonate-derived metabolic pathways.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12628221&dopt=Abstract montelukast, Singulair




Montelukast (singulair) for allergic rhinitis.

.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12637892&dopt=Abstract montelukast, Singulair