Single Dose Of Montelukast Research Articles

PROTECTIVE EFFECT OF MONTELUKAST AGAINST PENTYLENETETRAZOLE-INDUCED ACUTE SEIZURES AND KINDLING IN MICE

Montelukast, a selective reversible cysteinyl leukotriene1 (CysLT1) receptor antagonist, is used in treatment of asthma, exercise induced-bronchospasm, allergic rhinitis and urticaria. It was shown to protect against cerebral ischemia/reperfusion injury. Objectives: To examine the possible anticonvulsant effect of montelukast, either alone or in combination with a known antiepileptic drug against pentylenetetrazole (PTZ)-induced seizures. Methods: 112 adult male Swiss albino mice were used in the study and divided into two main groups, each containing 5 subgroups (Gp). The first main PTZ model (PTZ-a) contains: Gp1 vehicle-treated group was injected with saline (10 ml/kg, intraperitoneally i.p. in a single dose ), Gp2 PTZ-control injected with a single dose of PTZ (60 mg/kg, i.p.), Gp3 injected with valproate (50 mg/kg, i.p.) 30 minutes before PTZ, Gp4 injected with a single dose of montelukast (10 mg/kg, i.p.) 30 minutes before PTZ and Gp5 injected with both montelukast and valproate 30 minutes before PTZ administration. The second main kindling model (PTZ-k) contains: Gp1 was injected with saline (i.p.) every other day for 17 days, Gp2 PTZ-kindled received 9 PTZ injections in a dose of (40 mg/kg, i.p.) on alternate days for 17 days, Gp3 injected with valproate (50 mg/kg, i.p.) for 17 days, 30 minutes before PTZ, Gp4 daily injected with montelukast (10 mg/kg, i.p.) for 17 days 30 minutes before PTZ and Gp5 received both montelukast (10 mg/kg, i.p.) and valproate (50 mg/kg, i.p.) daily for 17 days, 30 minutes before administration of PTZ. Results: Single and repeated PTZ administration produced stage 4 seizures associated with a significant reduction in the brain level of reduced glutathione (GSH), concomittent with significant elevation in the brain levels of malondialdehyde (MDA), inteleukin1β (IL1β), tumor necrosis factor α (TNFα) and leukotriene D4 (LtD4). The use of valproate alone and its combination with montelukast suppressed the incidence of stage 4 seizures in acute PTZ induced convulsion while montelukast, valproate and their combination decreased the percentage of animals reaching stage 4 seizures in kindled mice. In both PTZ acute and kindled models, montelukast, valproate and their combined administration significantly elevated brain level of GSH and significantly decreased brain levels of MDA, IL1β, TNFα and LtD4 as compared to PTZ control groups. Interestingly, co-administration of valproate and montelukast resulted in a significant elevation in the brain level of GSH concomitant with a significant reduction in the brain levels of MDA, IL1β, TNFα and LtD4 as compared to each of the valproate and the montelukast groups in both models. Conclusion: Montelukast, either alone or in combination with valproate protects against PTZ induced seizures via blockade of leukotreine receptors & amelioration of oxidative stress and inflammatory cascades.

Adverse events are rare after single-dose montelukast exposures in children

Study objective: Montelukast sodium is a leukotriene-receptor antagonist approved as a controller medication for chronic asthma and allergic rhinitis in children and adults. We sought to characterize adverse events associated with single montelukast exposures in children ages 5–17 years and to determine whether adverse events were dose related for all-dose and for ultra-high-dose (≥50 mg) exposures.Methods: This is a retrospective analysis of data from the National Poison Data System for exposures that included montelukast in individuals aged 5–17 years for calendar years 2000–2016. Filters were applied to identify exposure events in which montelukast was the primary exposure and for which the exact or lowest-possible ingested dose was recorded. Characteristics of adverse events were examined using descriptive statistics and multivariable logistic models were used to examine whether associations of montelukast and adverse events were dose related.Results: During the 17-year study period, there were 17,069 montelukast exposures available for analyses. Patients were median [interquartile range] age 7 (5, 9) years, and 10,907 (64%) male gender. Abdominal pain was the most common adverse event (0.23%). There were 618 ultra-high-dose exposures (≥50 mg). These patients had median age 6 (5, 8) years, and 347 (56%) male gender. Abdominal pain was the most common adverse event (1.46%). Increasing ingested dose was associated with abdominal pain (adjusted odds ratio, 1.01, 95% confidence interval 1.01, 1.02) after adjustment for age and gender. No serious or life-threatening events were reported.Conclusions: Single-dose exposures of montelukast up to 445 mg are rarely associated with any adverse events and are not associated with serious or life-threatening adverse events in children aged 5–17 years.

Can a single dose response predict the effect of montelukast on exercise-induced bronchoconstriction?

Exercise-induced bronchoconstriction (EIB) can be prevented by a single dose of montelukast (MLK). The effect is variable, similar to the variable responsiveness observed after daily treatment with MLK. We hypothesized that the effect of a single MLK-dose (5 or 10 mg) on EIB could predict the clinical effectiveness of longer term once daily treatment. This was a prospective, open-label study. Twenty-four asthmatic adolescents (12-17 years) suboptimally controlled by low-dose inhaled corticosteroids, with ≥10% post-exercise fall in FEV1 , were included. They performed an exercise test at baseline, 20 hr after a single MLK-dose and 40-44 hr after the last dose of 4 weeks once daily treatment. The correlations between the effect of a single dose and 4 weeks treatment on area under the curve (AUC) and maximum % fall in FEV1 were calculated. AUC0-20 min decreased significantly after a single MLK-dose (P = 0.001, CI: 64.9-218.2), but not after 4 weeks of treatment (P = 0.080, CI: -12.2 to 200.4). There was a moderate correlation between the effect of a single MLK-dose and 4 weeks treatment on AUC0-20 min , r = 0.49 (P = 0.011), and maximum % fall in FEV1 , r = 0.40 (P = 0.035). The protection provided by a single MLK-dose against EIB only modestly predicts the effect of regular treatment against EIB in adolescent asthmatics on low-dose inhaled corticosteroids. If used on a daily base, MLK offered clinically significant protection against EIB in two thirds of adolescents suboptimally controlled by low-dose ICS.

Onset and duration of attenuation of exercise-induced bronchoconstriction in children by single-dose of montelukast

Single-dose montelukast attenuates exercise-induced bronchoconstriction (EIB) in adults within 2 hours postdose and lasting through 24 hours. This study evaluated the onset and duration of EIB attenuation in children after a single dose of montelukast. A randomized, double-blind, placebo-controlled, two-period crossover study was performed. Patients (n = 66) aged 4-14 years, with preexercise forced expiratory volume in 1 second of (FEV(1)) ≥70% predicted and maximum percentage fall in FEV(1) of ≥20% at two screening exercise challenges were eligible. Patients were to receive single-dose montelukast (4 or 5 mg) or placebo before performing standardized exercise challenges at 2 and 24 hours postdose. A 3- to-7-day washout separated the two crossover periods. The primary end point was maximum percentage fall in FEV(1) after exercise challenge 2 hours postdose. Secondary end points included maximum percentage fall in FEV(1) after the 24-hour postdose challenge; each of the following at 2 and 24 hours postdose-maximum percentage fall in FEV(1) categorized as <10%, 10-20%, or >20%; area under the curve (AUC) during 60 minutes postchallenge; time to recovery of FEV(1) to within 5% of preexercise baseline; and need for rescue medication. The mean maximum percentage fall in FEV(1) after the 2-hour postdose exercise challenge was significantly attenuated after single-dose montelukast compared with placebo (15.35% versus 20.00%; p = 0.020). Montelukast was also significantly more effective than placebo for maximum percentage fall after the 24-hour challenge (12.92% versus 17.25%; p = 0.005), the categorized maximum percent fall in FEV(1) at 2 hours (p = 0.034), and AUC at 2 hours (p = 0.022) and 24 hours (p = 0.013). Single-dose montelukast provided rapid and sustained EIB attenuation in children. Clinicaltrials.gov identifier: NCT00534976.

Protection against Exercise-Induced Bronchoconstriction Two Hours after a Single Dose of Montelukast in Children

Protection against Exercise-Induced Bronchoconstriction Two Hours after a Single Dose of Montelukast in Children

Baseline Predictors of Placebo Response in Exercise-Induced Bronchoconstriction (EIB): Pooled Regression Analysis >From Three Studies of Montelukast in EIB

Background. Exercise-induced bronchoconstriction (EIB) can be variable in its presentation and severity. Evaluating patterns of placebo response and patient-related factors driving placebo response could facilitate more efficient clinical trials for EIB. Methods. Data were pooled from three randomized, double-blind, crossover trials evaluating single-dose montelukast 10 mg or placebo in patients (N = 160) 15–45 years of age with EIB, defined as maximum % fall in forced expiratory volume in one second (FEV1) ≥20% after two screening exercise challenges. Serial exercise challenges were performed at 2, 8.5–12, and 24 h postdose. The authors evaluated the distribution and variability of placebo response. They also evaluated possible drivers of response, analyzing all baseline patient demographic and prerandomization screening visit pulmonary function data as single covariates in a simple univariate regression model for maximum % fall in FEV1 while on placebo at 2 h postdose. All covariates with p values <.1 were entered into both stepwise forward and backward regression procedures to select the “best” model. Results. Placebo response was variable, and showed a significant non-normal distribution (p < .001). Significant predictors of a greater response to placebo included: higher screening FEV1 % predicted (p <.001), smaller maximum % fall in FEV1 in screening (p < .001), shorter time to recovery in screening (p = .007), more asthma-related health care visits in the previous year (p = .004), older age (p = .001), less frequent asthma awakenings in the previous month (p = .003), and less frequent asthma symptoms in the past year (p = .011). Conclusion. Predictors of a larger placebo response were generally markers of less severe asthma and/or EIB. This may be related to EIB variability, spontaneous improvement, or the extent of placebo response relative to the outcomes in less severe patients.

The Targeted Oral, Once‐Daily Phosphodiesterase 4 Inhibitor Roflumilast and the Leukotriene Receptor Antagonist Montelukast Do Not Exhibit Significant Pharmacokinetic Interactions

This nonrandomized, fixed-sequence, 3-period study investigated potential pharmacokinetic interactions between the leukotriene receptor antagonist montelukast, approved for the treatment of asthma, and roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor in clinical development for asthma and chronic obstructive pulmonary disease. Pharmacokinetic interactions are of interest because both drugs may be coadministered and share a common metabolic pathway via cytochrome P450 3A. Single-dose montelukast (10 mg, po) was administered alone in period 1, followed by repeated once-daily roflumilast alone (500 microg, po) for 12 days (period 2). In period 3, 500 microg qd roflumilast was coadministered with 10 mg qd montelukast for 8 days. Different pharmacokinetic parameters were evaluated for montelukast alone, for steady-state roflumilast and its pharmacologically active metabolite roflumilast N-oxide alone, for single-dose montelukast when coadministered with steady-state roflumilast, and for steady-state roflumilast and its N-oxide metabolite when coadministered with steady-state montelukast. The AUC and Cmax of montelukast were modestly increased by 9% and 8%, respectively, when single-dose montelukast was coadministered with steady-state roflumilast. The pharmacokinetics of roflumilast and roflumilast N-oxide in steady state remained unchanged when repeat-dose montelukast was coadministered at steady-state. Concomitant administration of both drugs was well tolerated. These findings suggest that no dose adjustment is warranted for either drug when roflumilast and montelukast are coadministered.

A Responder Analysis Of Montelukast Compared With Placebo For Protection Against Exercise-Induced Bronchoconstriction - Pooled Results From 3 Studies

A single dose of montelukast has demonstrated efficacy to prevent exercise-induced bronchoconstriction (EIB). A “responder/nonresponder” analysis was performed using efficacy data pooled from 3 similar studies.

Single-Dose Montelukast or Salmeterol as Protection Against Exercise-Induced Bronchoconstriction

It has been previously established that montelukast provides protection against exercise-induced bronchoconstriction (EIB) after a single dose. The present objective was to assess the onset and duration of this protective action in a trial that included both positive and negative controls. A randomized, active-controlled and placebo-controlled, double-blind, double-dummy, three-way crossover study was conducted in 47 patients (age range, 15 to 44 years) in whom there was a 20 to 40% fall in FEV(1) following exercise (DeltaFEV(1)). In randomized sequence, patients received oral montelukast (10 mg), placebo, or inhaled salmeterol (50 microg) as a positive control. Dosing was followed by exercise challenges at 2, 8.5, and 24 h. The primary end point was maximum DeltaFEV(1) at 2 h postdose. Secondary end points included maximum DeltaFEV(1) at the two later time points, and other measures (including recovery time and need for beta-agonist rescue) at all time points. The maximum DeltaFEV(1) magnitudes at 2, 8.5, and 24 h were significantly smaller after montelukast administration than after placebo administration (least squares mean [+/- SE], 13.2 +/- 1.2%, 11.7 +/- 1.2%, and 10.0 +/- 1.1% vs 21.8 +/- 1.2%, 16.8 +/- 1.3%, and 14.0 +/- 1.1%, respectively; p <or= 0.001, < 0.01, and < 0.05). All secondary end point results supported the primary end point. Montelukast and salmeterol had similar efficacy at 2 and 8.5 h, but only montelukast was effective at 24 h. Montelukast provided significant protection against EIB having an onset within 2 h following a single oral dose and lasting for at least 24 h.

Prevention of Exercise-induced Bronchoconstriction by a Single Dose of Montelukast or Salmeterol

RATIONALE: Montelukast prevents exercise-induced bronchoconstriction (EIB) at the end of a once-daily dosing interval with repeated/chronic dosing. Data on prevention of EIB by a single oral dose of montelukast are limited, particularly in relation to other long-acting agents.

Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast

Leukotriene modifiers have been shown to protect against exercise-induced bronchoconstriction (EIB) with repeated, chronic dosing. To study the onset and duration of protection against EIB after a single dose of montelukast, a leukotriene receptor antagonist. In this randomized, crossover, double-blind study, 51 adult asthma patients with EIB (> or = 20% postexercise decrease in forced expiratory volume in 1 second [FEV1]) received a single oral dose of montelukast (10 mg), or placebo followed by exercise challenge 2, 12, and 24 hours after dosing. The primary end point was maximum percentage decrease in FEV1 from preexercise baseline during 60 minutes after the 2-hour challenge. At 2, 12, and 24 hours after dosing, the maximum decrease in FEV1 was 10.8% +/- 7.9%, 8.4% +/- 7.5%, and 8.3% +/- 7.3% for montelukast and 22.3% +/- 13.1%, 16.1% +/- 10.2%, and 16.9% +/- 11.7% for placebo, respectively (P < or = .001 at each time point). Postexercise recovery was quicker with montelukast than with placebo (P < or = .001); mean (95% confidence interval) differences were -26.8 minutes (-35.1 to -18.4 minutes), -16.0 minutes (-22.9 to -9.2 minutes), and -17.4 minutes (-24.9 to -9.9 minutes) at the 3 time points, respectively. At all time points, area under the curve for percentage decrease in FEV1 during 60 minutes after exercise was smaller after montelukast (P < or = .001); montelukast protected more patients against EIB (P < or = .001). Fewer patients required postexercise beta-agonist rescue at 2 hours after dosing with montelukast (P = .03). Montelukast provided significant protection against EIB as soon as 2 hours after a single oral dose, with persistent benefit up to 24 hours.

Onset and duration of single-dose protection of montelukast against exercise-induced bronchospasm

RATIONALE: Exercise-induced bronchospasm (EIB) is a common manifestation of asthma. The leukotriene-receptor antagonist montelukast has been shown to protect against EIB with repeated/chronic dosing. This study, in contrast, investigated the onset and duration of protection against EIB by a single dose of montelukast.

Bronchoconstriction Provoked by Exercise in a High-Particulate-Matter Environment is Attenuated by Montelukast

Airborne ultrafine and fine particulate matter (PM1 from fossil-fueled internal combustion engines may cause abnormal airway narrowing. Because of high PM1 exposure from ice resurfacing machines, the ice-rink athlete is especially vulnerable to PM1 toxicity. The purpose of this study was to evaluate protection by a single dose of montelukast in college ice hockey players following PM1 exposure exercise. Nine male ice hockey players (age 19.3 ± 1.22 yr) performed 4 randomized, double-blinded, high-intensity, 6-min cycle ergometer trials in low [PM1] (2260 ± 500 particles/cm3) and high [PM1] (348,600 ± 121,600 particles/cm3) after placebo or montelukast. Pre- and postspirometry showed similar peak FEV1 (forced expiratory volume in 1 s) falls between placebo and montelukast after low [PM1] trials (14.5 ± 18.06 vs. 9.5 ± 11.75% of baseline, respectively). Peak FEV1 falls after high [PM1] trials were greater for placebo than for montelukast (17.3 ± 9.79% vs. 1.7 ± 5.77% of baseline; p < .0001). High [PM1] FEV1 fall after exercise following montelukast ingestion was less than after exercise following placebo ingestion under high and low [PM1] conditions and after exercise following montelukast ingestion under low [PM1] conditions at 5, 10, and 15 min postchallenge (p < .004, .0006, .009, respectively). Montelukast provided greater protection against bronchoconstriction after exercise during high [PM1] than low [PM1] exposure (∼90% vs. ∼35%), suggesting that bronchoconstriction from PM1 exposure is predominately leukotriene mediated. The precise mechanism of airborne PM1-induced leukotriene-mediated airway narrowing remains unclear.

Montelukast, a Cysteinyl Leukotriene Receptor-1 Antagonist, Dose- and Time-Dependently Protects against Focal Cerebral Ischemia in Mice

Our previous studies showed that cysteinyl leukotriene receptor-1 (CysLT₁) antagonist pranlukast has a neuroprotective effect on cerebral ischemia in rats and mice. However, whether the neuroprotective effect of pranlukast is its special action or a common action of CysLT₁ receptor antagonists remains to be clarified. This study was performed to determine whether montelukast, another CysLT₁ receptor antagonist, has the neuroprotective effect on focal cerebral ischemia in mice, and to observe its dose- and time-dependent properties. Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Montelukast was injected intraperitoneally either as multiple doses (once a day for 3 days and 30 min before MCAO) or as a single dose (at 30 min before, 30 min after, or 1 h after MCAO), respectively, and pranlukast and edaravone were used as controls. The neurological deficits, infarct volumes, brain edema, neuron density, and Evans blue extravasation in the brain were determined 24 h after MCAO. Pretreatments with multiple doses or a single dose of montelukast (0.1 and 1.0 mg/kg) before MCAO significantly attenuated all the ischemic insults. Post-treatment with a single dose of montelukast (0.1 and 1.0 mg/kg) at 30 min after MCAO also significantly decreased brain edema and infarct volume, but not neurological deficits. However, post-treatment with a single dose of montelukast at 1 h after MCAO had no significant effect. Pranlukast showed the same effects as montelukast, but edaravone attenuated the ischemic insults only with multiple doses before MCAO. Thus, montelukast has a dose- and time-dependent neuroprotective effect on permanent focal cerebral ischemia in mice, with an effective dose range of 0.1–1.0 mg/kg and a therapeutic window of 30 min. These findings further support the therapeutic potential of CysLT₁ receptor antagonists in the treatment of cerebral ischemia at earlier phases.

Montelukast Has No Ergogenic Effects During Cycling in Sub-Freezing Conditions

0119 Montelukast (ML), a leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction (EIB) and its symptoms; however, little is known regarding the acute influence of ML on exercise performance. PURPOSE: To examine the effects of ML on physical performance in EIB- and EIB+ athletes. METHODS: Thirty athletes (27 male, 3 female) performed a 6-min time trial in sub-freezing conditions (−2.5 ± 0.4°C) using an electronically braked cycle ergometer to obtain total work accumulated (kJ). Subjects performed the exercise challenge twice (6–8 hours after either ML or placebo) and were evaluated for EIB following each exercise trial. RESULTS: No significant differences were found in work accumulated between placebo and treatment trials for pooled subjects (90.5 ± 18.6 and 91.7 ± 15.6 kJ, respectively) or subjects grouped according to EIB status (93.5 ± 19.7 and 95.2 ± 14.8 kJ for EIB- subjects, respectively; 83.3 ± 14.3 and 83.6 ± 14.9 kJ for EIB+ subjects, respectively). CONCLUSIONS: A single dose of ML had no ergogenic effect for EIB- and EIB+ subjects performing short-duration high intensity exercise in sub-freezing conditions. Supported by Merck and Co., Inc. grant #SING-US-63-01

Effectiveness of Single-Dose Montelukast on Airway Hyperresponsiveness During Cold Air Exercise and Eucapnic Voluntary Hyperventilation

1563 Montelukast (ML), a cysteinyl-leukotriene receptor antagonist, is indicated for prophylaxis and treatment of asthma. Its protective effect against airway hyperresponsiveness (AHR) as a single dose has not been thoroughly investigated. PURPOSE: To evaluate the effectiveness of ML in reducing AHR post-exercise (EX) and post-eucapnic voluntary hyperventilation (EVH). METHODS: A randomized, placebo-controlled, double blind, cross-over study was performed with 11 physically active AHR positive subjects (8 males, 3 females; age: 22.8 ± 6.8 yrs; ht: 173.9 ± 6.3cm; wt: 80.4 ± 15.7kg). 10mg ML or placebo (PL) was given orally six hours prior to each of two challenges: 1) a 6-minute, cold air (−3°C) maximal effort work accumulation cycle ergometer challenge; and 2) EVH, breathing 5% CO2, 21% O2, balance N2 at a rate of 85% MVV for 6 minutes. Spirometry was performed before and 5, 10, and 15 min post-challenge. A period of at least 48 hours was observed between challenges. RESULTS: No differences in post-challenge lung function were found between EX and EVH. Cold air EX and EVH resulted in significant falls in FEV1 (22.4 ± 18.0 and 24.2 ± 17.6, respectively, p<0.05). Falls in FEV1 after ML were less than PL (12.0 ± 10.9 and 14.4 ± 11.2 for EX and EVH, respectively, p<0.05). ML provided moderate protection against AHR (55% and 51%, p<0.05) for 8 of 11 EX subjects and 10 of 11 EVH subjects; no protection was afforded for 3 EX and 1 EVH challenged subjects. CONCLUSIONS: Both the EX and EVH challenges were potent stimuli of AHR. A single dose of ML provides reasonable protection in attenuating AHR from either EX or EVH. The lack of complete protection suggests multiple mediator involvement in AHR. Alternatively, better protection may be obtained from daily dose ML. Supported by Merck and Co., Inc. grant #SING-US-63-01.

Effectiveness of Single-Dose Montelukast on Airway Hyperresponsiveness During Cold Air Exercise and Eucapnic Voluntary Hyperventilation

Effectiveness of Single-Dose Montelukast on Airway Hyperresponsiveness During Cold Air Exercise and Eucapnic Voluntary Hyperventilation

Montelukast protects against nasal lysine-aspirin challenge in patients with aspirin-induced asthma

Rationale We evaluated the dose-response for montelukast (ML) against nasal lysine-aspirin (L-ASA) challenge in patients with aspirin-induced asthma (AIA). Methods 12 AIA patients were randomized in double-blind cross-over fashion to receive single doses of ML 10 mg (ML10), ML 40 mg (ML40), or placebo (PL), with L-ASA challenge performed 12 hours post-dosing. Measurements of peak nasal inspiratory flow (PNIF), nasal blockage visual analogue scale (VAS) and FEV 1 were made over 120 minutes after L-ASA challenge. Results Pre-challenge values for mean (SEM) PNIF (l/min) were not significantly different comparing all groups; ML10: 132 (10), ML40: 125 (12) and PL: 132 (11). The maximum % PNIF fall from baseline was significantly greater ( p<0.05) with PL: 45 (6) vs. ML10: 34 (6) or ML40: 32 (5). There was also a significantly greater ( p<0.05) average % PNIF response over 120 minutes after L-ASA challenge for PL: 26 (7) vs. ML10: 14 (6) or ML40: 17 (6). There were no significant differences for the maximum or average % PNIF fall from baseline comparing ML10 vs. ML40. There was a significant increase ( p<0.05) in VAS between baseline and 60 minutes or 120 minutes with PL, but not with ML10 or ML40. There were no significant differences for either the maximum or average % FEV 1 over 120 minutes as change from baseline comparing all groups. Conclusion A single dose of ML 10mg partially protected against the local effects of nasal L-ASA challenge, without further benefit at 40 mg. Nasal L-ASA challenge appeared to be a reproducible and safe method in assessing patients with AIA.