| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PEDIATRICS |
From Merck Research Laboratories, Rahway, New Jersey (Dr Knorr, Dr Maganti, Dr Ramakrishnan, Dr Tozzi, Dr Migoya); the Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, and the Departments of Pediatrics and Pharmacology, University of Missouri-Kansas City, Kansas City, Missouri (Dr Kearns).
Address for reprints: Barbara Knorr, MD, Merck Research Laboratories, Respiratory & Allergy Department, RY34B-332, 126 East Lincoln Avenue, Rahway, NJ 07065; e-mail: Barbara_knorr{at}merck.com.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
|---|
), maximum plasma concentration (Cmax), and time to Cmax (tmax) of montelukast 4-mg oral granules were investigated in infants aged 3 to 6 months. Montelukast concentrations were quantitated after a single 4-mg dose of montelukast oral granules. Pharmacokinetic parameters were determined using a population-based approach with a nonlinear mixed-effect, 1-compartment model with first-order absorption and elimination. Ninety-five percent confidence intervals for the AUCpop ratio (3 to 6 months/6 to 24 months) were determined. Safety and tolerability were assessed. Montelukast 4-mg oral granules in children 3 to 6 months of age yielded systemic exposure (AUCpop = 3644.3 ± 481.5 ng·h/mL) similar to that observed in children aged 6 to 24 months (3226.6 ± 250.0 ng·h/mL). Systemic exposure after a 4-mg dose of montelukast as oral granules is similar in children aged 3 to 6 months and 6 to 24 months.
Key Words: Bronchiolitis • population pharmacokinetics • controlled clinical trial • pediatrics
Montelukast, a potent orally active CysLT1 receptor antagonist, has demonstrated efficacy in the treatment of asthma symptoms in adults5 and children,6,7 in attenuating exercise-induced bronchoconstriction in adults8 and children,9 and in relieving symptoms of seasonal allergic rhinitis.10-13 In addition, recently published results from a randomized, placebo-controlled study in children aged 3 to 36 months hospitalized with RSV-induced bronchiolitis demonstrated treatment with montelukast (5-mg crushed chewable tablet), compared with placebo, was associated with significant improvement in the respiratory symptoms subsequent to RSV-induced bronchiolitis, suggesting that montelukast may provide benefit in this disease.14
Given viral-induced bronchiolitis affects very young children, including those under 6 months of age, and based on the potential role of CysLTs in the pathophysiology of this disorder, there may be a putative role for montelukast in its treatment.14 It is therefore important that the pharmacokinetic properties and safety of montelukast be evaluated in this population. Thus, the purpose of this study was to evaluate both the pharmacokinetics of montelukast after a single, 4-mg oral dose and the apparent safety of 2 multiple-dose regimens (4 mg and 8 mg) in infants with active bronchiolitis or a history of bronchiolitis and respiratory symptoms. The effect of age on montelukast disposition was examined by comparison of the pharmacokinetic parameters with results obtained from a prior study (using identical doses and experimental approaches) conducted in older infants and children ranging in age from 6 to 24 months.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
The study protocol was approved by the ethical committees of the respective clinical institutions that participated in the investigation at 3 sites: Chile (San Borja Arriaran Hospital), Columbia (Fundación Santa Fe de Bogotá), and Peru (Instituto Especializado de Salud del Niño), South America. Before the initiation of any study-related procedure, written informed consent was obtained from parents or guardians of all patients.
Study Design
This was a multicenter, randomized, 3-period, 14-day study evaluating the multiple-dose safety of the 4-mg and 8-mg oral granules doses of montelukast and the population pharmacokinetics of montelukast after administration of a single oral 4-mg dose of oral granules in patients aged 3 to 6 months. During all 3 periods, study drug was administered as 2 packets (packet A [montelukast or placebo] and packet B [montelukast or placebo]) of the oral granules formulation. Packets were administered sequentially on a tablespoonful (approximately 15 gm) of applesauce.
Patients were evaluated for study inclusion at a prestudy visit (visit 1) 3 to 7 days before the beginning of the study, at which time a physical examination was performed, vital signs were obtained, and blood samples were collected for safety evaluations and pretreatment montelukast plasma concentration assays.
Period 1 (study day 1) was a single-blind, 1-day pharmacokinetic period in which all patients received a single witnessed dose of 4-mg montelukast oral granules. During period 1, patients were randomly assigned to 1 of 2 possible sparse plasma sampling schedules: A (n = 9; samples at predose and 2.5, 6, and 10 hours postdose) and B (n = 5; samples at predose and 2, 4, and 24 hours postdose).
Period 2 (study days 2 through 7) was a double-blind, placebo-controlled, 6-day treatment period designed to assess safety in which all patients received either montelukast 4-mg oral granules or matching-image oral granules placebo administered once daily in the morning. Period 2 began with a witnessed dose of study medication in the clinic after the 24-hour plasma sample for period 1 was obtained. Caregivers administered blinded study drug for the following 5 days at the same time each morning and completed a daily medication diary card recording dosing times and drug consumption.
Period 3 (study days 8 through 14) was a double-blind, placebo-controlled, 7-day safety period in which all patients received either montelukast 8-mg oral granules or matching-image oral granules placebo administered once daily in the morning. Patients returned to the study center on day 8 to begin period 3, in which they received a witnessed dose of study medication in the clinic and then were discharged from the study center. Caregivers administered blinded study drug for the following 5 days a t the same time each morning and completed a daily medication diary card recording dosing times and drug consumption. On study day 14, patients returned to the study center, where they received a final, witnessed dose of study drug and were then discharged to home.
During all 3 study periods, patients were allowed to have treatment with inhaled or nebulized albuterol or salbutamol, inhaled or nebulized cromolyn, and inhaled or nebulized, oral, or parenteral corticosteroids for the treatment of viral-induced bronchiolitis and worsening asthma-like symptoms. Use of oral ß-agonists was also permitted once the pharmacokinetic sampling in period 1 had been completed.
Dose Selection
Initial dose selection was based on the assumption that systemic montelukast exposure associated with beneficial effects in treatment of asthma in children would represent a reasonable target exposure for infants with respiratory symptoms (eg, cough, wheeze) associated with viral-induced bronchiolitis. Because the goal of therapy with montelukast in the treatment of viral-induced bronchiolitis would be to treat underlying inflammation-associated respiratory symptoms, it is reasonable to extrapolate that the clinically effective dose of montelukast in asthma in this age group (4-mg oral granules) would be efficacious in the treatment of the respiratory symptoms subsequent to viral-induced bronchiolitis. As well, previous studies suggested a favorable safety profile for the 4-mg oral granules dose in children aged 6 to 24 months with asthma15,16 and for a crushed 5-mg tablet in children aged 3 to 36 months with bronchiolitis.14 Given the wide therapeutic index of montelukast and prior experience with the drug in pediatric populations,6,15 it was anticipated that both the 4-mg and 8-mg doses would be well tolerated in patients aged 3 to 6 months.
Because planned efficacy studies of montelukast included a dose-ranging study, 2 doses (ie, 4 mg and 8 mg) of the drug administered as oral granules were initially evaluated in patients aged 3 to 6 months before initiating larger efficacy studies in this pediatric subpopulation. To facilitate comparison of the pharmacokinetic data to those previously obtained in patients 6 to 24 months of age,17 the 4-mg dose of montelukast granules was selected for pharmacokinetic evaluation in the current study.
Montelukast Assay
At each sampling time according to the schedules described above, 3-mL blood samples were drawn into evacuated blood collection tubes containing sodium heparin as the anticoagulant. Blood was centrifuged immediately, and the plasma fraction (
1.5 mL) was transferred to opaque cryotubes that were protected from light and stored at -70°C until shipment for assay. Plasma concentrations were determined by a high-pressure liquid chromatography (HPLC) assay method. The assay procedure was found to be selective for montelukast, and no detectable interferences at the retention times for the analyte or internal standard were found in plasma double blank samples. Briefly, a 300-µL plasma sample was prepared for analysis by the addition of an internal standard, followed by protein precipitation with 400 µL of acetonitrile. The sample was vortexed for 30 seconds and then injected into an Agilent 1100 system (Agilent Technologies, Palo Alto, Calif) for HPLC analysis. Montelukast and the internal standard were separated through an Apex octadecyl column (4.6 x 50 mm, 3 µm) using a mobile phase of acetonitrile/ammonium phosphate (0.05 M, ph 3.5; 61:39 volume/volume) and detected via a Shimadzu fluorescence detector (Shimadzu Corp, Kyoto, Japan) at excitation/emission wavelengths of 350/400 nm. Retention times were 3.2 minutes for montelukast and 4.0 minutes for internal standard. The dicyclohexylamine (DCHA) salt form of montelukast was used as the standard; all results were reported as nanograms of free montelukast per milliliter of plasma.
The lower limit of quantitation for this assay was 3 ng/mL, with a linear calibration range of 3.0 to 964 ng/mL for montelukast. Two sets of low (4.8 ng/mL), middle (48.2 ng/mL), and high (482 ng/mL) quality control samples were assayed together with study samples in an assay run. The assay accuracy obtained in the quality control samples ranged from 104.9% to 105.8% of the nominal values for montelukast. Assay precision in the quality control samples ranged from 0.31% to 0.84% coefficient of variation. All assays were performed at the Merck Research Laboratories Drug Metabolism Department (West Point, Pa).
Pharmacokinetics and Statistical Methods
A population pharmacokinetic approach using a nonlinear, mixed-effect, 1-compartment model with first-order absorption, and elimination was fitted to the available montelukast plasma concentration-time data. The pharmacokinetic model and validation thereof have been described elsewhere.18 This approach was based on the assumption that montelukast would exhibit linear pharmacokinetic properties in this age range, similar to those previously observed in older children and adults.19,20 An identical population pharmacokinetic approach was used for the previous study in patients aged 6 to 24 months,17 who served as the historical control group for the purpose of comparison of pharmacokinetic parameters in the current study to assess possible age dependence in montelukast disposition across the 3- to 24-month age range. In addition, the data from patients aged 3 to 6 months were pooled with the historical data from 6- to 24-month-old patients, and pharmacokinetic parameter estimates were calculated for 3- to 24-month-old patients.
The following pharmacokinetic parameter estimates were obtained after administration of a single 4-mg dose of montelukast oral granules: population area under the concentration-time curve (AUCpop), clearance/bioavailability (CL/F), maximum observed concentration (Cmax), time of Cmax (tmax), and apparent elimination half-life (t
). Population AUC was the primary parameter used for relative comparison of montelukast dose-exposure between the 3- to 6-month-old age group and the 6- to 24-month-old historical controls17 and also in the calculation of the ratios for comparison between the groups. Ratios were determined using 2 age-related subsets from the historical control group (ie, 6- to 12-month-olds and 6- to 24-month-olds). Ninety-five percent (95%) confidence intervals (CIs) for the AUCpop ratios (3 to 6 months/children 6 to 24 months [historical data] and 3 to 6 months/children 6 to 12 months [historical data]) were calculated. Data from patients aged 3 to 6 months were pooled with the historical data from patients aged 6 to 24 months,17 and population estimates for pharmacokinetic parameters (AUCpop, CL/F, Cmax, tmax, and apparent t) for patients 3 to 24 months old also were calculated.
The individual pharmacokinetic parameter estimates (AUC from time zero to infinity [AUC0-], Cmax, CL/F, tmax, and apparent t) obtained from the population modeling described above were used to conduct formal statistical comparisons between the 2 age groups (3- to 6-month-olds vs 6- to 24-month-olds). These comparisons were made by comparing appropriately transformed parameter estimates (eg, AUC0-, Cmax, and CL/F were log transformed; tmax was rank transformed and apparent t was transformed by taking its reciprocal) using a 2-tailed, Student t test with the significance limit set at 
= .05.
To further explore the association between development and montelukast disposition, both AUC0- and apparent elimination t were examined as a function of age for patients over a range of 3 to 24 months. Pearson correlation coefficients and corresponding statistics were generated from linear and nonlinear (where appropriate) regressions between age and the pharmacokinetic parameters.
Safety Evaluations
A physical examination was performed 3 to 7 days before administration of the study drug in period 1 and on study day 14 (period 3). Clinical laboratory tests (hematology and serum chemistry) were performed 3 to 7 days before administration of the study drug in period 1, on study day 8 (period 2), and on study day 14 (period 3). Vital sign measurements, including blood pressure, heart rate, respiratory rate, and oral or tympanic temperature, were evaluated 3 to 7 days before drug administration, 6 times during period 1, and both predose and postdose on study days 8 and 14 of periods 2 and 3, respectfully. Adverse experiences were recorded by the investigator, who determined the severity and causal relationship to study medication.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
Pharmacokinetics
Population AUC estimates with 95% CIs after administration of a single 4-mg dose of oral granules in patients aged 3 to 6 months, 6 to 12 months, 6 to 24 months,17 and 3 to 24 months (pooled data) are presented in Table II. The mean ratios for AUCpop for patients 3 to 6 months of age were comparable to those for patients 6 to 24 months (ratio = 1.13) and 6 to 12 months of age (ratio = 1.05).
|
Table III contains summary data for other montelukast population pharmacokinetic parameters (Cmax, tmax, apparent t, and CL/F) from the current study (patients aged 3 to 6 months), the previous investigation conducted in infants and children aged 6 to 24 months17 and 2 other populations created from the aforementioned data sets (ie, ages 6 to 12 months and 3 to 24 months). The values for AUC0-, Cmax, CL/F, tmax, and apparent t after a single 4-mg oral montelukast dose did not appear to differ significantly among the age groups (P > .800). No statistically significant (P > .400) relationships or apparent trends were observed when AUC0- (Figure 1) and apparent t estimates (Figure 2) were examined as a function of age (eg, Pearson correlation coefficient = -.13 and .10 for AUC0- and apparent t, respectively).
|
|
|
Safety and Tolerability
Twenty-four clinical adverse experiences were reported in 8 patients, and 3 laboratory adverse experiences were reported in 3 patients. There were no serious adverse experiences, and no patient discontinued study participation because of a clinical or laboratory adverse experience. The most common clinical adverse experiences were asthma, diarrhea, and loose stools. Six adverse experiences were determined by the investigators to be possibly drug related (4 mg montelukast: diarrhea, loose stools, nausea; 8 mg montelukast: diarrhea, loose stools; placebo: diarrhea). The 3 reported laboratory adverse experiences were anemia (8 mg montelukast [2 patients]; placebo [1 patient]), none of which was considered serious or drug related.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
This study demonstrated that multiple doses of 4 mg montelukast, followed by 8-mg doses, given over 14 days were generally well tolerated in infants. Similar to montelukast dose-ranging studies (ie, 2 to 200 mg) in adults,20 no apparent dose-related adverse experiences were identified in this study. Adverse experiences determined by the investigator to be related to study therapy occurred at both doses of montelukast and in the placebo group. Moreover, the safety profile observed in this age group was similar to that observed in older children7,17,19 and adults.5
Very young children have limited blood volumes, and collection of blood samples to support classical pharmacokinetic analyses in the youngest patients often presents a technical and logistical challenge. To address this challenge, a sparse sampling scheme (ie, 2 sampling schedules with 1 predose and 3 postdose samples), followed by use of a population pharmacokinetic analysis approach, was used, as was done in a previous study in patients 6 to 24 months of age.17 This approach enabled accurate estimation of patient-specific pharmacokinetic parameters sufficient to explore potential age effects on montelukast disposition.
Montelukast is metabolized in the liver by the cytochrome P450 enzyme system (CYP) and specifically, by CYP3A4 and CYP2C9 isoforms.22 As previously reviewed,23 pharmacokinetic data from studies using substrates of CYP3A4 and CYP2C9 suggest the potential for increased plasma clearance in young children and, consequently, the need for age-specific dosing schemes to produce an extent of systemic exposure likely to yield comparable drug efficacy and safety observed for adults. In contrast, data from the present study and previous investigations of montelukast disposition17,24 do not apparently support marked developmental differences in the age range down to 3 months.
As illustrated by the data in Tables II and III, montelukast pharmacokinetics from our study cohort after a single 4-mg dose were similar to those obtained in previous pediatric studies17 that used an identical dose and approach to study. As well, our finding of no apparent association between age and montelukast pharmacokinetic parameters suggests that development does not produce marked differences in the disposition of this drug in infants and children between 3 and 24 months of age.
The implications of our pharmacokinetic data for young infants and those for young children up to 24 months of age reside with the apparent dose-exposure-response relationship for montelukast. For the beneficial effects of montelukast in asthma, a target exposure appears to range between 2569 and 3226.6 ng/h.mL (based on the mean geometric AUC) for both adults and children.17 Given the previously reported dose proportionality in montelukast pharmacokinetics25 and the apparent similarity in both the dose-exposure profile (Table II) and the disposition of this drug in infants and young children (Table III), it would appear that a fixed dose of the drug may be sufficient for further evaluating the safety and efficacy of montelukast in young infants with postviral bronchiolitis.
In conclusion, the present study demonstrated that both a 4-mg and 8-mg oral granule dose of montelukast was well tolerated in patients aged 3 to 6 months. As well, the pharmacokinetics of the drug over this age range was similar to those in older infants and young children.
The authors thank Dr Theodore F. Reiss for his careful review of this article. Investigators for this study were Maria Boza, MD, Santiago, Chile; Elida Dueñas, MD, Bogota, Colombia; Frances Guerra Lilo, MD, Lima, Peru. This study was funded by a grant from Merck Research Laboratories, Rahway, New Jersey.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Parrott RH, Kim HW, Arrobio JO, et al. Epidemiology of respiratory syncytial virus infection in Washington, D.C. II: infection and disease with respect to age, immunologic status, race and sex. Am J Epidemiol. 1973;98: 289-300.
2. Sigurs N, Bjarnason R, Sigbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med. 2000;161: 1501-1507.
3. Volovitz B, Faden H, Ogra PL. Release of leukotriene C4 in respiratory tract during acute viral infection. J Pediatr. 1988; 112: 218-222.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. van Schaik SM, Tristram DA, Nagpal IS, Hinta KM, Welliver IRC, Welliver RC. Increased production of IFN-Y and cysteinyl leukotrienes in virus-induced wheezing. J Allergy Clin Immunol. 1999;103: 630-636.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB, for the Montelukast Clinical Research Study Group. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med. 1998;158: 1213-1220.
6. Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics. 2001;108: E48.
7. Knorr B, Matz J, Bernstein JA, et al, for the Pediatric Montelukast Study Group. Montelukast for chronic asthma in 6- to 14-year-old children. JAMA. 1998;279: 1181-1186.
8. Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med. 1998;339: 147-152.
9. Kemp JP, Dockhorn RJ, Shapiro GG, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr. 1998;133: 424-428.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Nayak AS, Philip G, Lu S, Malice M-P, Reiss TF, and the Montelukast Fall Rhinitis Investigator Group. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall. Ann Allergy Asthma Immunol. 2002;88: 592-600.[Web of Science][Medline] [Order article via Infotrieve]
11. Philip G, Malmstrom K, Hampel FC Jr, et al. Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy. 2002;32: 1020-1028.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. van Adelsberg J, Philip G, LaForce CF, et al. Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2003;90: 214-222.[Web of Science][Medline] [Order article via Infotrieve]
13. van Adelsberg J, Philip G, Pedinoff AJ, et al. Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period. Allergy. 2003;58: 1268-1276.[CrossRef][Medline] [Order article via Infotrieve]
14. Bisgaard H, for the Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med. 2003;167: 379-383.
15. van Adelsberg J, Moy J, Wei LX, Tozzi CA, Knorr B, Reiss TF. Safety, tolerability and exploratory efficacy of montelukast in 6- to 24-month old patients with asthma. Curr Med Res Opin. 2005;21: 971-979.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. van Adelsberg J, Montalvo J, Liu N, Knorr B, Wei LX, Reiss TF. Safety and tolerability of montelukast, a leukotriene receptor antagonist in >6 to <31 month old asthmatic patients: evaluation at 3 months. Am J Respir Crit Care Med. 2003;167: A271.
17. Migoya E, Kearns GL, Hartford A, et al. Pharmacokinetics of montelukast in asthmatic patients 6 to 24 months old. J Clin Pharm. 2004;44: 487-494.[CrossRef]
18. Nguyen H, Zhang J, Larson P, Knorr B. Use of the population one-compartment model to design a study to best estimate the AUC with limited number of time points per patient. Clin Pharmacol Ther. 1998;63: 195.
19. Knorr B, Nguyen HH, Kearns GL, et al. Montelukast dose selection in children ages 2 to 5 years: comparison of population pharmacokinetics between children and adults. J Clin Pharm. 2001;41: 612-619.
20. Altman LC, Munk Z, Seltzer J, et al, for the Montelukast Asthma Study Group: a placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. J Allergy Clin Immunol. 1998;102: 50-56.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140: 543-546.
22. Chiba M, Xu X, Nishime JA, Balani SK, Lin JH. Hepatic microsomal metabolism of montelukast, a potent leukotriene D4 receptor antagonist in humans. Drug Metab Dispos. 1997;25: 1022-1031.
23. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349: 1157-1167.
24. Muijsers RBR, Noble S. Montelukast: a review of its therapeutic potential in asthma in children 2 to 14 years of age. Pediatr Drugs. 2002;4: 123-139.
25. Knorr B, Holland S, Rogers JD, Nguyen HH, Reiss TF. Montelukast adult (10-mg film-coated tablet) and pediatric (5-mg chewable tablet) dose selections. J Allergy Clin Immunol. 2000;106: S117-S178.[CrossRef]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  I. Amirav, A. S. Luder, N. Kruger, Y. Borovitch, I. Babai, D. Miron, M. Zuker, G. Tal, and A. Mandelberg A Double-Blind, Placebo-Controlled, Randomized Trial of Montelukast for Acute Bronchiolitis Pediatrics, December 1, 2008; 122(6): e1249 - e1255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Bisgaard, A. Flores-Nunez, A. Goh, P. Azimi, A. Halkas, M.-P. Malice, J.-L. Marchal, S. B. Dass, T. F. Reiss, and B. A. Knorr Study of Montelukast for the Treatment of Respiratory Symptoms of Post-Respiratory Syncytial Virus Bronchiolitis in Children Am. J. Respir. Crit. Care Med., October 15, 2008; 178(8): 854 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sveinbjornsson, A. Rasmuson, N. Baryawno, M. Wan, I. Pettersen, F. Ponthan, A. Orrego, J. Z. Haeggstrom, J. I. Johnsen, and P. Kogner Expression of enzymes and receptors of the leukotriene pathway in human neuroblastoma promotes tumor survival and provides a target for therapy FASEB J, October 1, 2008; 22(10): 3525 - 3536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Kearns, S. Lu, L. Maganti, X. Li, E. Migoya, T. Ahmed, B. Knorr, and T. F. Reiss Pharmacokinetics and Safety of Montelukast Oral Granules in Children 1 to 3 Months of Age With Bronchiolitis J. Clin. Pharmacol., April 1, 2008; 48(4): 502 - 511. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, 3 to 6 months; 
, 6 to 24 months.