Montelukast Sodium

Montelukast Sodium (MK-0476) is a selective, reversible antagonist of leukotriene receptor with the Ki values of 0.52nM in U937 cell [1].

Montelukast Sodium has been reported to inhibit leukotriene D4 receptor specific binding in U937 cell, guinea pig lung and sheep lung with the Ki values of 0.52nM, 0.18nM and 4nM, respectively. In addition, Montelukast Sodium has also shown the inhibitory effect with the IC50 of 10mM for leukotriene C3 in U937 cell membranes and 40mM for leukotriene B4 in THP-1 cell membranes. Apart from these, after oral treatment of Montelukast Sodium, it has been revealed to suppress leukotriene D4 receptor induced bronchoconstriction in conscious squirrel monkeys with ED50 value of 0.03±0.001mg/kg [1].

References:
[1] Jones TR1, Labelle M, Belley M, Champion E, Charette L, Evans J, Ford-Hutchinson AW, Gauthier JY, Lord A, Masson P, et al. Pharmacology of montelukast sodium (Singulair), a potent and selective leukotriene D4 receptor antagonist. Can J Physiol Pharmacol. 1995 Feb;73(2):191-201.

Formulation and evaluation of a montelukast sodium orally disintegrating tablet with a similar dissolution profile as the marketed product.[Pubmed:26654222]

Pharm Dev Technol. 2017 Mar;22(2):168-172.

A major challenge of orally disintegrating tablet (ODT) development is predicting its bioequivalence to its corresponding marketed product. Therefore, comparing ODT dissolution profiles to those of the corresponding marketed product is very important. The objective of this study was to develop a 5.2-mg Montelukast Sodium (MS) ODT with a similar dissolution profile to that of the marketed chewable tablet. Dissolution profiles were examined in different media to screen each formulation. We found that MS dissolution from ODTs in acidic medium heavily depended on manufacturing methods. All MS ODTs prepared using direct compression rapidly disintegrated in acidic medium. However, dispersed MS powders aggregated into sticky masses, resulting in slow dissolution. In contrast, MS ODTs prepared using wet granulation had much faster dissolution rates in acidic medium with no obvious aggregation. Additionally, the optimized formulation, prepared using wet granulation, displayed similar dissolution profiles to the marketed reference in all four types of media examined (f2 > 50). The in vitro disintegration time of the optimized ODT was 9.5 +/- 2.4 s, which meets FDA requirements. In conclusion, the wet granulation preparation method of MS ODTs resulted in a product with equivalent dissolution profiles as those of the marketed product.

[Effect of montelukast sodium intervention on airway remodeling and percentage of Th17 cells/CD4+CD25+ regulatory T cells in asthmatic mice].[Pubmed:27817787]

Zhongguo Dang Dai Er Ke Za Zhi. 2016 Nov;18(11):1174-1180.

OBJECTIVE: To study the dynamic changes in the percentage of Th17 cells/CD4(+)CD25(+) regulatory T cells after intervention with Montelukast Sodium, a leukotriene receptor antagonist, in asthmatic mice and the association between them. METHODS: Balb/c mice were randomly divided into blank group, asthma group, and Montelukast Sodium group. The asthmatic mouse model of airway remodeling was established by sensitization with intraperitoneal injection of chicken ovalbumin (OVA) and aluminum hydroxide suspension and aerosol inhalation of OVA. The mice in the blank group were given normal saline, and those in the Montelukast Sodium group were given Montelukast Sodium by gavage before aerosol inhalation. Eight mice were randomly sacrificed within 24 hours after 2, 4, and 8 weeks of aerosol inhalation. The pathological sections of lung tissue were used to observe the degree of airway remodeling. Flow cytometry was used to measure the percentages of Th17 cells and CD4(+)CD25(+) regulatory T cells in CD4(+) T cells. RESULTS: The asthma group and the Montelukast Sodium group had significantly higher bronchial wall thickness and smooth muscle thickness at all time points compared with the blank group (P<0.05). At 8 weeks of intervention, the Montelukast Sodium group had significantly greater improvements in the above changes compared with the asthma group (P<0.05). Compared with the blank group, the asthma group and the Montelukast Sodium group had significant increases in Th17 cells (positively correlated with airway remodeling) and significant reductions in CD4(+)CD25(+) regulatory T cells (negatively correlated to airway remodeling) at all time points (P<0.05). At 8 weeks of intervention, the Montelukast Sodium group had a significant reduction in the number of Th17 cells and a significant increase in the number of CD4(+)CD25(+) regulatory T cells compared with the asthma group (P<0.05). CONCLUSIONS: Montelukast Sodium intervention can alleviate airway remodeling and achieve better improvements over the time of intervention. The possible mechanism may be related to the improvement of immunologic derangement of CD4(+)CD25(+) regulatory T cells and inhibition of airway inflammation.

Novel montelukast sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats.[Pubmed:26983932]

Arch Pharm Res. 2016 Apr;39(4):539-546.

To develop a Montelukast Sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats, several Montelukast Sodium-loaded suspensions were prepared with a suspending agent, stabilizers and anti-aggregation agents, and their stabilities were investigated by visually observing the sedimentation phenomenon and determining the concentration of the degradation product. Moreover, dissolution and pharmacokinetic studies of the optimized formulation were examined in rats compared to commercial Montelukast Sodium-loaded granules. Avicel RC-591 (Avicel), a suspending agent, prevented the sedimentation of these suspensions at >2.496 (w/v) per cent composition. Amongst the stabilizers tested, fumaric acid provided the lowest concentration of montelukast sulphoxide (a degradation product) in these suspensions at 40 degrees C, demonstrating its excellent stabilizing activity. Furthermore, as an anti-aggregation agent, glycerin gave lower amounts of degradation product than those with poloxamer 407 and Tween 80. In particular, montelukast-loaded oral suspension, an aqueous suspension containing Montelukast Sodium/Avicel/fumaric acid/glycerin at a concentration of 312/2496/15.6/62.4 (mg/100 ml), and the commercial granules exhibited similar dissolution profiles in 0.5% (w/v) aqueous solution of sodium lauryl sulphate. Moreover, the pharmacokinetics in rats provided by this suspension was comparable to that of the commercial granules, suggesting that they were bioequivalent. In addition, it was physically and chemically stable at 40 degrees C for at least 6 months. Thus, this Montelukast Sodium-loaded oral suspension, with bioequivalence to the commercial granules and excellent stability, could be a prospective dosage form for the treatment of asthma.

[Therapeutic effect and safety of montelukast sodium combined with budesonide in children with cough variant asthma: a Meta analysis].[Pubmed:27817773]

Zhongguo Dang Dai Er Ke Za Zhi. 2016 Nov;18(11):1100-1105.

OBJECTIVE: To evaluate the therapeutic effect and safety of Montelukast Sodium combined with budesonide in children with cough variant asthma. METHODS: The databases CNKI, Wanfang Data, VIP, PubMed, EMbase, and BioMed Central were searched for randomized controlled trials (RCTs) of Montelukast Sodium combined with budesonide in the treatment of children with cough variant asthma. Data extraction and quality assessment were performed for RCTs which met the inclusion criteria, and RevMan 5.3 software was used to perform quality assessment of the articles included and Meta analysis. RESULTS: A total of 11 RCTs involving 1 097 patients were included. The results of the Meta analysis showed that compared with the control group (inhalation of budesonide alone), the observation group (inhalation of Montelukast Sodium combined with budesonide) had significantly higher overall response rate and more improved pulmonary function parameters including forced expiratory volume in the first second, percentage of forced expiratory volume in the first second, and peak expiratory flow, as well as significantly lower recurrence rate (P<0.01). The incidence of adverse events showed no significant difference between the two groups. CONCLUSIONS: Inhalation of Montelukast Sodium combined with budesonide has a significant effect in children with cough variant asthma and does not increase the incidence of adverse events.

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug.[Pubmed:26506265]

Nat Commun. 2015 Oct 27;6:8466.

As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias.

Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood-brain barrier dysfunction.[Pubmed:25090924]

Neuroscience. 2014 Sep 26;277:859-71.

Current evidence suggests that inflammation plays a role in the pathophysiology of seizures. In line with this view, selected pro-inflammatory arachidonic acid derivatives have been reported to facilitate seizures. Kainate-induced seizures are accompanied by leukotriene formation, and are reduced by inhibitors of LOX/COX pathway. Moreover, LTD4 receptor blockade and LTD4 synthesis inhibition suppress pentylenetetrazol (PTZ)-induced kindling and pilocarpine-induced recurrent seizures. Although there is convincing evidence supporting that blood-brain-barrier (BBB) dysfunction facilitates seizures, no study has investigated whether the anticonvulsant effect of montelukast is associated with its ability to maintain BBB integrity. In this study we investigated whether montelukast and other CysLT receptor antagonists decrease PTZ-induced seizures, as well as whether these antagonists preserve BBB during PTZ-induced seizures. Adult male albino Swiss mice were stereotaxically implanted with a cannula into the right lateral ventricle, and two electrodes were placed over the parietal cortex along with a ground lead positioned over the nasal sinus for electroencephalography (EEG) recording. The effects of montelukast (0.03 or 0.3 mumol/1 muL, i.c.v.), pranlukast (1 or 3 mumol/1 muL, i.c.v.), Bay u-9773 (0.3, 3 or 30 nmol/1 muL, i.c.v.), in the presence or absence of the agonist LTD4 (0.2, 2, 6 or 20 pmol/1 muL, i.c.v.), on PTZ (1.8 mumol/2 muL)-induced seizures and BBB permeability disruption were determined. The animals were injected with the antagonists, agonist or vehicle 30 min before PTZ, and monitored for additional 30 min for the appearance of seizures by electrographic and behavioral methods. BBB permeability was assessed by sodium fluorescein method and by confocal microscopy for CD45 and IgG immunoreactivity. Bay-u9973 (3 and 30 nmol), montelukast (0.03 and 0.3 mumol) and pranlukast (1 and 3 mumol), increased the latency to generalized seizures and decreased the mean amplitude of EEG recordings during seizures. LTD4 (0.2 and 2 pmol) reverted the anticonvulsant effect of montelukast (0.3 mumol). Montelukast (0.03 and 0.3 mumol) prevented PTZ-induced BBB disruption, an effect that was reversed by LTD4 at the dose of 6 pmol, but not at the doses 0.2 and 2 pmol. Moreover, the doses of LTD4 (0.2 and 2 pmol) that reverted the effect of montelukast on seizures did not alter montelukast-induced protection of BBB, dissociating BBB protection and anticonvulsant activity. Confocal microscopy analysis revealed that 1. PTZ increased the number of CD45+ and double-immunofluorescence staining for CD45 and IgG cells in the cerebral cortex, indicating BBB leakage with leukocyte infiltration; 2. while LTD4 (6 pmol) potentiated, montelukast decreased the effect of PTZ on leukocyte migration and BBB, assessed by double-immunofluorescence staining for CD45 and IgG cells in the cannulated hemisphere. Our data do not allow us ruling out that mechanisms unrelated and related to BBB protection may co-exist, resulting in decreased seizure susceptibility by montelukast. Notwithstanding, they suggest that CysLT1 receptors may be a suitable target for anticonvulsant development.