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Study Of Montelukast for theTreatment of Respiratory Symptoms of Post-RSV-Bronchiolitis in Children.
Am J Respir Crit Care Med. 2008 Jun 26;
Bisgaard H, Flores-Nunez A, Goh A, Azimi P, Halkas A, Malice MP, Marchal JL, Dass SB, Reiss TF, Knorr BA
Rationale A pilot study (Bisgaard et al. AJRCCM 2003;167:379) had reported the efficacy of montelukast in post-RSV-bronchiolitic respiratory symptoms. Objectives To evaluate efficacy and safety of montelukast 4 and 8 mg in treating recurrent respiratory symptoms of post-RSV-bronchiolitis in children in a large, multicenter study. Methods This was a double-blind study of 3-24-month-old children who had been hospitalized for a first or second episode of physician-diagnosed RSV-bronchiolitis and testing positive for RSV. Patients (n=979) were randomized to placebo, montelukast 4 or 8 mg/day for 4 weeks (Period-I) and 20 weeks (Period-II). The primary endpoint was percentage symptom-free days (%SFD; day with no daytime cough, wheeze and shortness of breath, and no nighttime cough). Results No significant differences were seen between montelukast and placebo in %SFD over Period-I: mean+/-SD for placebo, montelukast 4 and 8 mg were 37.0+/-30.7, 38.6+/-30.4, and 38.5+/-29.9, respectively. Least-squares mean differences [95% CI] between montelukast 4 mg and placebo and between montelukast 8 mg and placebo were 1.9% [-2.9, 6.7] and 1.6% [-3.2, 6.5]. Secondary endpoints were similar across treatments. Both doses were generally well tolerated. During the first two treatment weeks, average %SFD was ~29%. In post-hoc analyses of patients (n=523) with persistent symptoms (%SFD
J Matern Fetal Neonatal Med. 2008 Jun; 21(6): 407-13
Demir K, Kumral A, Duman N, Sarioglu S, Yilmaz O, Yesilirmak DC, Kargi A, Ozkan H
Objective. We aimed to assess the efficiency of clarithromycin, montelukast, and pentoxifylline treatments, alone and in combination, in reducing hyperoxic lung injury at the histopathologic level. Methods. The experiment was carried out with 47 newborn rat pups divided into six groups during postnatal days 3 to 13. The rats belonging to group 1 were designated as the control group and kept in room air without exposure to hyperoxia. Group 2 (clarithromycin), group 3 (montelukast), group 4 (pentoxifylline), group 5 (clarithromycin + montelukast + pentoxifylline combination), and group 6 (placebo) were kept in plexiglass chamber and exposed to hyperoxia (88-92%) throughout the experiment. Alveolar surface area percentage, fibrosis, and smooth muscle actin expression were assessed in the lungs, which were resected by thoracotomy on postnatal day 14. Results. Drug treatments, when used separately, were not detected to be superior to placebo with regard to mean alveolar surface area, fibrosis, and smooth muscle actin expression. Combination treatment resulted in significantly higher mean lung area percentages and lower actin scores with respect to the placebo treatment group (64.0% vs. 50.2%, p=0.002; 0 (0-1) vs. 7 (2-12), p=0.005, respectively). Conclusions. It was determined that clarithromycin, montelukast, and pentoxifylline combination treatment is superior to placebo treatment in the newborn rat hyperoxic lung injury model. The present study indicates that combination therapy might be successful in bronchopulmonary dysplasia, which has complex pathophysiologic processes and lacks established efficient treatment strategies.
Allergol Int. 2008 Jul 1; 57(3):
Okubo K, Baba K
Background: Secretion of nasal discharge was enhanced and airway-resistance in the nasal cavity was augmented, resulting in nasal congestion, when leukotrienes were administered to the nasal mucosa. These results indicate that leukotrienes play an important role in the pathogenesis of allergic rhinitis. Methods: A double-blind clinical study was carried out to evaluate the efficacy and the safety of montelukast, a cysteinyl leukotriene receptor 1 antagonist, 5mg, 10mg or placebo orally administered once daily at bedtime for 2 weeks, to Japanese patients with seasonal allergic rhinitis. The composite nasal symptom scores (average over the 2-week treatment period) were compared among the montelukast 5mg and 10mg groups with the placebo group. Results: The composite nasal symptom score significantly improved in the montelukast 5mg and 10mg groups compared with the placebo group. The administration of montelukast 5mg or 10mg once daily was well tolerated and the safety profiles were similar to those of the placebo. There were no significant differences in the incidences of adverse experience or drug-related adverse experience among the montelukast 5mg, 10mg groups and the placebo group. Conclusions: Both montelukast 5mg and 10mg doses show clinically meaningful efficacy for the treatment of patients with seasonal allergic rhinitis and the safety profiles of those are comparable to that of the placebo.
Eosinophilic oesophagitis: a common cause of dysphagia in young adults?
Int J Clin Pract. 2008 Jul; 62(7): 1096-107
Basavaraju KP, Wong T
Eosinophilic oesophagitis (EO) is an increasingly recognised chronic, relapsing inflammatory condition of the oesophagus. There has been a mini-epidemic of EO in the last decade. The incidence of this condition is higher in children and is commoner in males. There is either a family or personal history of atopic conditions present in a significant number of patients and can also be familial in up to 10%. The classical symptom in an adult is chronic, intermittent solid-food dysphagia and food impaction, often necessitating emergency endoscopic removal. Despite the history of dysphagia for a number of years, patients remain well with no weight loss, which can mislead clinicians to diagnose a functional problem with a resulting delay in the diagnosis. There are various endoscopic features of EO; commonly multiple rings and linear furrows, though these can be subtle and the mucosa may be macroscopically normal. The hallmark of this condition is the histological presence of > or =15 eosinophils/high power field (HPF) in the oesophageal mucosa. Therapeutic options include avoidance of dietary allergens, topical or systemic steroids, Montelukast, Mepolizumab (anti-IL-5 antibody) and endoscopic dilation of strictures unresponsive to medical therapy.
Pharm Res. 2008 Jun 17;
Okumu A, Dimaso M, Löbenberg R
PURPOSE: The objectives of the study was to develop a dissolution test method that can be used to predict the oral absorption of montelukast sodium, and to establish an in vitro/in vivo correlation (IVIVC) using computer simulations. METHODS: Drug solubility was measured in different media. The dissolution behaviour of montelukast sodium 10 mg film coated tablets was studied using the flow-through cell dissolution method following a dynamic pH change protocol, as well as in the USP Apparatus 2. Computer simulations were performed using GastroPlustrade mark. Biorelevant dissolution media (BDM) prepared using bile salts and lecithin in buffers was used as the dissolution media, as well as the USP simulated intestinal fluid (SIF) pH 6.8 and blank FaSSIF pH 6.5. Dissolution tests in the USP Apparatus 2 were performed under a constant pH condition, while the pH range used in the flow through cells was pH 2.0 to 7.5. The in vitro data were used as input functions into GastroPlustrade mark to simulate the in vivo profiles of the drug. RESULTS: The solubility of montelukast sodium was low at low pH, but increased as the pH was increased. There was no significant difference in solubility in the pH range of 5.0 to 7.5 in blank buffers, but the drug solubility was higher in biorelevant media compared with the corresponding blank buffers at the same pH. Using the flow through cells, the dissolution rate was fast in simulated gastric fluid containing 0.1% SLS. The dissolution rate slowed down when the medium was changed to FaSSIF pH 6.5 and increased when the medium was changed to FaSSIF medium at pH 7.5. In the USP Apparatus 2, better dissolution was observed in FaSSIF compared with the USP buffers and blank FaSSIF with similar pH values. Dissolution was incomplete with less than 10% of the drug dissolved in the USP-SIF, and was practically non existent in blank FaSSIF pH 6.5. The in vitro results of the dynamic dissolution test were able to predict the clinical data from a bioavailability study best. CONCLUSIONS: Dynamic dissolution testing using the flow through cell seems to be a powerful tool to establish in vitro/in vivo correlations for poorly soluble drugs as input function into GastroPlus.
Trends in medication use for asthma among children.
Curr Opin Allergy Clin Immunol. 2008 Jun; 8(3): 232-7
Phillips C, McDonald T
PURPOSE OF REVIEW: To review recent studies of changing medication use for asthma among children. RECENT FINDINGS: Although many countries monitor mortality and hospitalizations related to asthma, there is less surveillance of medication use for asthma. Since the late 1990s, and in the United States, Australia and the United Kingdom, there has been a change in the medications used to prevent asthma in childhood, with an increase in inhaled corticosteroids, and a decrease in mast cell stabilizers. Prescriptions for montelukast have increased four-fold in the United Kingdom for children since 2000, with similar increases in the United States and in Australia. There has been a trend in some countries to increased use of fixed dose combined long-acting beta-agonist/inhaled corticosteroid products; in Australia and the United Kingdom, fixed dose combinations now account for the majority of preparations containing inhaled steroids prescribed to children with asthma. SUMMARY: Studies in a number of countries have shown marked secular trends in asthma medications for children since the late 1990s. Research needs to employ serial cross-sectional studies in the same population to capture changing medication use and to be precise about types of medication within a class. The changes in many countries indicate a greater concordance with guidelines.
Magnes Res. 2008 Mar; 21(1): 38-42
Nechifor M, Cuciureanu M, Chelarescu D, Ciubotariu D, Pascu M
We tested the influence of magnesium, zinc and copper upon the montelukast (MK, antagonist of cysteinyl leukotriene receptor type 1) effect in experimentally-induced thermoalgesia. We worked on 5 groups of 10 adults, each Wistar rats, that received: group I-control; group II: MK (10 mg/kg) unique administration; group III: MgCl2 (1 mM/kg/day) i.p., 3 days and MK (10 mg/kg) unique administration on the 3rd day; group IV: ZnCl2, (0.1 mM/kg/day), i.p., 3 days and MK (10 mg/kg) unique administration on the 3rd day; group V: copper acetate (0.05 mM/kg/day), i.p., 3 days and MK (10 mg/kg) unique administration on the 3rd day. We determined the thermoalgesic sensitivity (TS) using a tail flick analgesia meter, initially, 3 days after daily cation administration and 3 hours after MK administration. Our data show that MK has a statistically significant reduction of TS vs control group (3.76 +/- 1.04 s vs 1.81 +/- 0.98 s, p < 0.05). Copper and magnesium administration do not significantly change the MK effect to decrease TS. The co-administration of zinc and MK statistically significantly increased the TS of the group that received only MK (2.51 +/- 0.21 s vs 3.76 +/- 1.04 s, p < 0.05). Animals that received only cations (in the above mentioned doses) did not significantly change TS.
Can Respir J. 2008 May-Jun; 15(4): 193-8
Gelb AF, Taylor CF, Shinar CM, Gutierrez CA, Zamel N
BACKGROUND: Monitoring noninvasive biomarkers of inflammation is an important adjunct in asthma therapy. OBJECTIVE: The goal of the present study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in asthmatic patients, and to evaluate the NO response to maintenance fluticasone 250 mug/salmeterol 50 mug (F/S) and add-on montelukast 10 mg (M). METHODS: Thirty (24 women) nonsmoking, mild to moderate asthmatic patients were studied, mean age (+/- SD) 43+/-9 years, treated with F/S for more than one year. All were clinically stable for longer than eight weeks and had not taken oral corticosteroids and/or leukotriene antagonists for eight weeks before the present study. Spirometry, Juniper asthma symptom score, fractional exhaled NO (FENO) 100 mL/s, bronchial NO and alveolar NO concentration (CANO) were measured in a single-blind, nonrandomized crossover study. Protocol: Visit 1: baseline F/S; visit 2: after four weeks of F/S plus M; visit 3: after four weeks of S plus M; and visit 4: after four weeks of S only. Values in asthmatic patients were also compared with 34 nonsmoking age-matched healthy controls with normal lung function. RESULTS: After 180 mug aerosolized metered dose inhaler albuterol, the forced expiratory volume in 1 s at baseline was 2.6+/-0.8 L (86%+/-16% of the predicted value) and the forced expiratory volume in 1 s over the forced vital capacity was 77%+/-9% (mean +/- SD), and was similar at visits 2 to 4. Juniper scores were mildly abnormal at visits 1 to 3, but significantly worse (P=0.03) at visit 4 versus visits 1 to 3. FENO values at visits 1 to 3 were similar but significantly increased (P=0.007) at visit 4. Bronchial NO was higher (P=0.03) at visit 4, versus visits 1 and 2, and was no different at visit 3. Compared with the healthy subjects, FENO and bronchial NO values were abnormal (greater than the normal mean plus 2 SD) in 33% of asthmatic patients at visits 1 to 3. CANO was similar for visits 1 to 4. CANO was abnormal (greater than the normal mean + 2 SD) in 20% of asthmatic patients. CONCLUSION: In clinically stable asthmatic patients, despite controller treatment including moderate-dose inhaled corticosteroids and add-on M, 33% of mild to moderate asthmatic patients have ongoing nonsuppressed bronchial sites of increased NO production, compared with healthy control subjects. These controllers have no effect on CANO, which was abnormal in 20% of the asthmatic patients studied. The addition of add-on M to baseline moderate-dose inhaled corticosteroid did not further reduce total exhaled, bronchial and/or alveolar NO production.
Pharmacogenet Genomics. 2008 Jul; 18(7): 551-558
Kang MJ, Lee SY, Kim HB, Yu J, Kim BJ, Choi WA, Jang SO, Hong SJ
BACKGROUND: IL-13 is a pivotal cytokine in allergic inflammation and bronchial hyperresponsiveness, and is known to influence leukotriene levels. OBJECTIVE: We investigated whether IL-13 polymorphisms may be associated with clinical phenotypes and drug responsiveness to the leukotriene receptor antagonist (LTRA) in Korean asthmatic children with exercise-induced bronchoconstriction (EIB). METHODS: We enrolled 242 normal controls and 374 patients with asthma. Of the asthmatic patients, 100 performed exercise challenge tests before and after receiving montelukast (5 mg/day) for 8 weeks and included 80 subjects in drug responsiveness analysis. We assessed IL-13 polymorphisms (-1512A/C, -1112C/T, +2044G/A) through PCR-restriction fragment length polymorphism analysis. RESULTS: Significantly higher total IgE levels and maximum percent fall in forced expiratory volume in 1 s (FEV1) (%) after exercise challenge test were found in asthmatic patients carrying one or two copies of the IL-13 +2044A versus those homozygous for +2044G (P=0.011 and 0.040, respectively). We further noted a correlation of total IgE with maximum percent fall in FEV1 (%) in asthmatic patients, as well as a reverse correlation with improvement of maximum percent fall in FEV1 (%) after exercise challenge tests. Finally, we observed a significant association between responsiveness to montelukast and IL-13 -1112C/T polymorphism and the haplotype of IL-13 polymorphisms. CONCLUSION: The IL-13 +2044G/A polymorphism may be associated with atopy and EIB severity in Korean children with EIB, and thus could potentially be considered as a disease-modifying gene. Moreover, the IL-13 -1112C/T polymorphism and the haplotype of IL-13 polymorphisms seem to be associated with LTRA drug responsiveness, and thus might prove useful as a target for modulation of LTRA drug responsiveness.
Real-life effectiveness of Singulair (montelukast) in 506 children with mild to moderate asthma.
Isr Med Assoc J. 2008 Apr; 10(4): 287-91
Amirav I
BACKGROUND: Based on the outcome of several randomized controlled trials, the orally active leukotriene receptor antagonist montelukast (Singulair, Merck) has been licensed for treatment of asthma. The drug is favored for treating childhood asthma, where a therapeutic challenge has arisen due to poor compliance with inhalation therapy. OBJECTIVES: To assess the efficiency of and satisfaction with Singulair in asthmatic children under real-life conditions. METHODS: Montelukast was prescribed for 6 weeks to a cohort of 506 children aged 2 to 18 years with mild to moderate persistent asthma, who were enrolled by 200 primary care pediatricians countrywide. Four clinical correlates of childhood asthma--wheeze, cough, difficulty in breathing, night awakening--were evaluated from patients' diary cards. RESULTS: Due to under-treatment by their physicians, almost 60% of the children were not receiving controller therapy at baseline. By the end of the study, which consisted of montelukast treatment, a significant improvement over baseline was noted in asthma symptoms and severity, as well as in treatment compliance. The participating pediatricians and parents were highly satisfied with the treatment. CONCLUSIONS: The results of this extensive study show that the use of montelukast as monotherapy in children presenting with persistent asthma resulted in a highly satisfactory outcome for themselves, their parents and their physicians.