Navafenterol (AZD8871) in healthy volunteers: safety, tolerability and pharmacokinetics of multiple ascending doses of this novel inhaled, long-acting, dual-pharmacology bronchodilator, in two phase I, randomised, single-blind, placebo-controlled studies.

BACKGROUND: Navafenterol (AZD8871) is a novel, long-acting, dual-pharmacology (muscarinic receptor antagonist and ß2-adrenoceptor agonist) molecule in development for chronic obstructive pulmonary disease and asthma. METHODS: These two phase I, randomised, single-blind, multiple-ascending-dose studies evaluated inhaled navafenterol and placebo (3:1 ratio) in healthy, male, non-Japanese (study A; NCT02814656) and Japanese (study B; NCT03159442) volunteers. In each study, volunteers were dosed in three cohorts, allowing gradual dose escalation from 300 µg to 600 µg to 900 µg. The primary objective was to investigate the safety and tolerability of navafenterol at steady state. Pharmacokinetics were also assessed. RESULTS: Twenty-four volunteers completed each study (navafenterol, n = 6; placebo, n = 2 in each cohort). There were no deaths, serious adverse events (AEs) or treatment-emergent AEs (TEAEs) leading to discontinuation of navafenterol. The most frequent TEAEs were vessel puncture-site bruise (placebo, n = 2; navafenterol 900 µg; n = 3) in study A and diarrhoea (placebo, n = 1; navafenterol 300 µg, n = 2; navafenterol 900 µg, n = 3) in study B. No dose-response relationship was observed for TEAEs. There was a dose-dependent increase in mean heart rate on day 16 in both studies. The pharmacokinetics of navafenterol were similar between non-Japanese and Japanese volunteers. CONCLUSIONS: Multiple ascending doses of navafenterol were well-tolerated and the safety and pharmacokinetics of navafenterol were similar in non-Japanese and Japanese volunteers. The findings support navafenterol clinical development. TRIAL REGISTRATION: ClinicalTrials.gov ; Nos.: NCT02814656 and NCT03159442; URL: www.clinicaltrials.gov .

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques.

Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of sterilizing immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans.

Detection of post-vaccination enhanced dengue virus infection in macaques: An improved model for early assessment of dengue vaccines.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques.

The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-γ and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

An adjuvanted, tetravalent dengue virus purified inactivated vaccine candidate induces long-lasting and protective antibody responses against dengue challenge in rhesus macaques.

The immunogenicity and protective efficacy of a candidate tetravalent dengue virus purified inactivated vaccine (TDENV PIV) formulated with alum or an Adjuvant System (AS01, AS03 tested at three different dose levels, or AS04) was evaluated in a 0, 1-month vaccination schedule in rhesus macaques. One month after dose 2, all adjuvanted formulations elicited robust and persisting neutralizing antibody titers against all four dengue virus serotypes. Most of the formulations tested prevented viremia after challenge, with the dengue serotype 1 and 2 virus strains administered at 40 and 32 weeks post-dose 2, respectively. This study shows that inactivated dengue vaccines, when formulated with alum or an Adjuvant System, are candidates for further development.

Ultrasound of metacarpophalangeal joints is a sensitive and reliable endpoint for drug therapies in rheumatoid arthritis: results of a randomized, two-center placebo-controlled study.

INTRODUCTION: We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA). METHODS: A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15 mg or 7.5 mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP). RESULTS: All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures. CONCLUSIONS: Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00746512.

A comparison of the natriuretic and kaliuretic effects of cicletanine and hydrochlorothiazide in prehypertensive and hypertensive humans.

OBJECTIVES: The aim of this study was to compare the single-dose effects of thiazide-type diuretics cicletanine and hydrochlorothiazide (HCTZ), on natriuresis and kaliuresis in prehypertensive and treatment-naïve, stage 1 hypertensive patients and to explore the impact of GRK4 gene polymorphisms on thiazide-induced urinary electrolyte excretion. METHODS: The study was a randomized, double-blind, placebo-controlled, three-period, four-treatment, balanced incomplete block, cross-over study in male patients assigned to treatment sequences consisting of placebo, cicletanine 50 mg, cicletanine 150 mg, and HCTZ 25 mg, doses used to treat hypertension. Cumulative urine samples were collected predosing and over 24 h after dosing in each period to compare urine electrolyte excretion profiles of potassium (UKV), sodium (UNaV), magnesium, calcium, phosphate, chloride, and pH among groups. Each treatment was administered to 18 different patients in each period, and an equal number of patients had less than and at least three GRK4 allele variants. RESULTS: Compared with placebo, mean UKV was significantly increased with HCTZ 25 mg (12.7 mmol/day; P ≤ 0.001), cicletanine 50 mg (4.6 mmol/day; P = 0.026), and cicletanine 150 mg (5.5 mmol/day; P = 0.011), and mean UNaV was significantly increased with HCTZ 25 mg (102.2 mmol/day; P ≤ 0.001), cicletanine 50 mg (21.7 mmol/day; P = 0.005), and cicletanine 150 mg (57.9 mmol/day; P ≤ 0.001). CONCLUSION: All treatments had more natriuresis, diuresis, and kaliuresis than placebo, and both doses of cicletanine had less kaliuresis than HCTZ. These findings suggest that cicletanine is a favorable and well tolerated option for the treatment of hypertension with an improved safety profile compared with HCTZ.

Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals.

OBJECTIVE: Use of glucocorticoids for anti-inflammatory efficacy is limited by their side effects. This study examined, in the same individuals, prednisone's acute, dose-dependent effects on inflammation as well as biomarkers of glucose regulation and bone homeostasis. DESIGN: In this randomized, double-blind, parallel-design trial of healthy adults demonstrating cutaneous allergen-induced hypersensitivity, patients received placebo or prednisone 10, 25 or 60 mg daily for 7 days. METHODS: Effects on peripheral white blood cell (WBC) count, ex vivo whole blood lipopolysaccharide (LPS)-stimulated TNF-α release and response to cutaneous allergen challenge were assessed concurrently with biomarkers for glucose tolerance and bone turnover. RESULTS: Differential peripheral WBC counts changed significantly within hours of prednisone administration. Ex vivo, LPS-stimulated TNF-α was significantly reduced by all prednisone doses on days 1 and 7. The late phase cutaneous allergen reaction was significantly reduced with prednisone 60 mg vs placebo on days 1 and 7. Oral glucose tolerance tests revealed significant increases in glycaemic excursion on days 1 and 7, whereas increases in insulin and C-peptide excursions were more notable on day 7 with all doses of prednisone. The bone formation markers osteocalcin, and procollagen I N- and C-terminal peptides decreased significantly on days 1 and 7 vs placebo. CONCLUSIONS: In healthy young adults after single doses as low as 10 mg, prednisone treatment has significant effects on glucose tolerance and bone formation markers within hours of treatment, in parallel with anti-inflammatory effects.

A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma.

BACKGROUND: Current treatments for acute asthma provide inadequate benefit for some patients. Intravenous montelukast may complement existent therapies. OBJECTIVE: To evaluate efficacy of intravenous montelukast as adjunctive therapy for acute asthma. METHODS: A total of 583 adults with acute asthma were treated with standard care during a < or = 60-minute screening period. Patients with FEV(1) < or =50% predicted were randomly allocated to intravenous montelukast 7 mg (n = 291) or placebo (n = 292) in addition to standard care. This double-blind treatment period lasted until a decision for discharge, hospital admission, or discontinuation from the study. The primary efficacy endpoint was the time-weighted average change in FEV(1) during 60 minutes after drug administration. Secondary endpoints included the time-weighted average change in FEV(1) at various intervals (10-120 minutes) and percentage of patients with treatment failure (defined as hospitalization or lack of decision to discharge by 3 hours postadministration). RESULTS: Montelukast significantly increased FEV(1) at 60 minutes postdose; the difference between change from baseline for placebo (least-squares mean of 0.22 L; 95% CI, 0.17, 0.27) and montelukast (0.32 L; 95% CI, 0.27, 0.37) was 0.10 L (95% CI, 0.04, 0.16). Similar improvements in FEV(1)-related variables were seen at all time points (all P <.05). Although treatment failure did not differ between groups (OR 0.92; 95% CI, 0.63, 1.34), a prespecified subgroup analysis suggests likely benefit for intravenous montelukast at US sites. CONCLUSION: Intravenous montelukast added to standard care in adults with acute asthma produced significant relief of airway obstruction throughout the 2 hours after administration, with an onset of action as early as 10 minutes.

Clinical studies of combination montelukast and loratadine in patients with seasonal allergic rhinitis.

BACKGROUND: Concomitant use of montelukast and loratadine may improve symptoms of seasonal allergic rhinitis (SAR) more than treatment with either drug alone. OBJECTIVE: We compared the efficacy of this combination versus placebo, nasal beclomethasone, montelukast, and loratadine in study 1 and versus placebo, montelukast, and loratadine in study 2. METHODS: Patients were randomly allocated to double-blind treatment with intranasal beclomethasone 200 mu g/twice daily (study 1 only), placebo, montelukast 10 mg+loratadine 10 mg, montelukast 10 mg, or loratadine 10 mg once daily. The primary endpoint was the Composite Symptom Score (CSS): average of daily diary scores for Daytime Nasal Symptoms and Nighttime Symptoms. RESULTS: In study 1, improvements in the change from baseline in CSS were seen for montelukast+loratadine (least-squares means [95% CI] = -0.43 [-0.51, -0.35]), beclomethasone (-0.57 [-0.64, -0.49]), montelukast, and loratadine. All treatments were significantly better than placebo; montelukast+loratadine had a significantly greater effect on CSS than montelukast alone but no difference compared to loratadine was detected. Beclomethasone provided significantly greater improvement versus montelukast+loratadine on the primary and secondary endpoints except for the rhinoconjunctivitis quality-of-life score. In study 2, the combination treatment was similar to montelukast, loratadine, and placebo for the primary and secondary endpoints. CONCLUSION: In study 1, montelukast+loratadine had a significantly greater effect on CSS than placebo and montelukast alone; however, in all comparisons, nasal beclomethasone had a greater effect on daily symptoms. In contrast, the combination of montelukast+loratadine in study 2 did not provide greater improvement compared with placebo, montelukast, or loratadine monotherapy, perhaps due to a large placebo effect.

Reports of suicidality in clinical trials of montelukast.

BACKGROUND: In recent years, a number of drugs and drug classes have come under scrutiny by the US Food and Drug Administration regarding suicidality (including suicidal behavior and ideation). OBJECTIVE: We sought to perform 2 reviews (requested by the US Food and Drug Administration) of the number of events possibly related to suicidality reported in Merck clinical trials of montelukast. METHODS: Method 1 was a descriptive review of clinical adverse experiences (AEs) from 116 studies (double-blind and open-label, adult and pediatric, and single- and multiple-dose studies) completed as of March 2008. Summaries were constructed from investigator-reported AE terms possibly related to suicidality (completed suicide, suicide attempt, and suicidal ideation) or self-injurious behavior. Method 2 used a retrospective adjudication of investigator-reported AEs and other events listed in the study database described as possibly suicidality-related adverse events (PSRAEs) in a prespecified set of 41 double-blind, placebo-controlled trials completed as of April 2008. RESULTS: No completed suicides were reported in any study. For the descriptive review, 20,131 adults and children received montelukast, 9,287 received placebo, and 8,346 received active control; AEs possibly related to suicidality were rare and were similar between the montelukast and placebo or active-control groups. For the adjudicated review across 22,433 patients, there were 730 adjudicated events. In 9,929 patients taking montelukast, 1 PSRAE was identified (classified as suicidal ideation); none were identified in 7,780 and 4,724 patients taking placebo and active control, respectively. CONCLUSIONS: Assessed by using 2 complementary methods, there were no reports of completed suicide, and reports of PSRAEs were rare in patients receiving montelukast and similar to those seen in control subjects.

Analysis of behavior-related adverse experiences in clinical trials of montelukast.

BACKGROUND: Frequencies of behavior-related adverse experiences (BRAEs) in controlled clinical studies of leukotriene modifier drugs have not been summarized. OBJECTIVE: We sought to compare the frequency of BRAEs in patients receiving montelukast or placebo in a retrospective analysis of Merck clinical trial data. METHODS: An adverse experience database was constructed to include all double-blind, placebo-controlled trials of montelukast meeting prespecified criteria. BRAEs (described using the Medical Dictionary for Regulatory Activities controlled vocabulary dictionary) were prespecified to include any term in the Psychiatric Disorders System Organ Class, selected terms related to general disorders, and terms related to akathisia. Frequencies of BRAEs (overall, leading to study discontinuation, and/or serious) were summarized. Analyses estimated the odds ratios (ORs) for montelukast versus placebo based on the frequency of patients with BRAEs in each study. RESULTS: In total 35 adult and 11 pediatric placebo-controlled trials were included; 11,673 patients received montelukast, 8,827 received placebo, and 4,724 received active control. The frequency of patients with 1 or more BRAEs was 2.73% and 2.27% in the montelukast and placebo groups, respectively; the OR for montelukast versus placebo was 1.12 (95% CI, 0.93-1.36). The frequency of patients with a BRAE leading to study discontinuation was 0.07% and 0.11% in the montelukast and placebo groups, respectively (OR, 0.52; 95% CI, 0.17-1.51). The frequency of patients with a BRAE considered serious was 0.03% in both treatment groups. CONCLUSION: Reports of BRAEs were infrequent in clinical trials of montelukast. Those leading to study discontinuation or considered serious were rare. Frequencies were similar regardless of treatment group.

Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children.

RATIONALE: A pilot study (Bisgaard H; 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) reported the efficacy of montelukast in post-respiratory syncytial virus (RSV) bronchiolitic respiratory symptoms. OBJECTIVES: To evaluate the 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- to 24-month-old children who had been hospitalized for a first or second episode of physician-diagnosed RSV bronchiolitis and who tested positive for RSV. Patients (n = 979) were randomized to placebo or to montelukast at 4 or 8 mg/day for 4 weeks (period I) and 20 weeks (period II). The primary end point was percentage symptom-free days (%SFD; day with no daytime cough, wheeze, and shortness of breath, and no nighttime cough). MEASUREMENTS AND MAIN RESULTS: No significant differences were seen between montelukast and placebo in %SFD over period I: mean +/- SD for placebo and for montelukast at 4 and 8 mg were 37.0 +/- 30.7, 38.6 +/- 30.4, and 38.5 +/- 29.9, respectively. Least-squares mean differences (95% confidence interval) 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), respectively. Secondary end points were similar across treatments. Both doses were generally well tolerated. During the first two treatment weeks, average %SFD was approximately 29%. In post hoc analyses of patients (n = 523) with persistent symptoms (%SFD < or = 30% over Weeks 1-2), differences in %SFD were seen between montelukast and placebo over Weeks 3-24: difference were 5.7 (0.0, 11.3) for montelukast (4 mg) minus placebo and 5.9 (0.1, 11.7) for montelukast (8 mg) minus placebo. CONCLUSIONS: In this study, montelukast did not improve respiratory symptoms of post-RSV bronchiolitis in children.

Onset of efficacy of montelukast in seasonal allergic rhinitis.

Montelukast has shown efficacy for seasonal allergic rhinitis (SAR); however, onset of action for SAR has not been presented. The aim of this study was to determine the onset of action of montelukast, 10 mg, measured in days after starting once-daily therapy, in spring and fall studies of SAR. Data were analyzed from four 2-week, double-blind, placebo-controlled phase III clinical trials. End points included the daytime nasal symptoms score, the nighttime symptoms score, the composite symptoms score (mean of the scores for daytime nasal symptoms and nighttime symptoms), and the daytime eye symptoms score. Using a 0-3 scale (no symptoms to severe symptoms), daytime symptoms were rated by patients once daily each evening; nighttime symptoms were rated once daily each morning. Analyses of data pooled across the four evening dosing studies showed that montelukast, compared with placebo, produced significant improvement (p < or = 0.001) from baseline by day 2 of treatment (after 2 doses) in the daytime nasal symptoms score, nighttime symptoms score, and composite symptoms score. Differences between montelukast and placebo for these end points in mean change from baseline at day 2 were -0.08 (95% CI, -0.12, -0.03), -0.08 (95% CI, -0.13, -0.04), and -0.08 (95% CI, -0.12, -0.04), respectively. These data represented a mean reduction for montelukast of 11-13% in symptom scores from baseline for each end point at day 2. When compared with the full 2-week response, these observed differences for each end point at day 2 (after 2 doses) represented a substantial proportion (over 70%) of the overall treatment benefits seen. Significant improvement (p < or = 0.001) in the daytime eye symptoms score was seen by day 1 (-0.08 [-0.12, -0.03]), after the first dose. In patients treated for SAR, montelukast has a beneficial effect on daytime and nighttime symptoms by the 2nd day of daily therapy.

Montelukast effectively treats the nighttime impact of seasonal allergic rhinitis.

BACKGROUND: Nighttime problems constitute a significant burden on the quality of life of patients with seasonal allergic rhinitis (SAR). The aim of this study was to evaluate the effectiveness of montelukast on nighttime AR symptoms. METHODS: In seven multicenter, double-blind, parallel-group trials, nighttime problems were assessed as the nighttime symptoms score (NSS), an average of three individual symptom scores: difficulty going to sleep, nighttime awakening, and nasal congestion on awakening (each rated 0 = none to 3 = severe). Patients (aged 15-82 years) were randomized to receive montelukast, 10 mg (n = 1751), placebo (n = 1557), or the positive control loratadine, 10 mg (n = 1616). RESULTS: In a combined analysis, changes from baseline (mean +/- SE) in NSS were -0.28 +/- 0.01, -0.16 +/- 0.01, and -0.24 +/- 0.01 for the montelukast, placebo, and loratadine groups, respectively. Difference versus placebo in least-squares mean change from baseline were -0.11 (95% confidence interval, -0.14, -0.08; p < or = 0.001) for montelukast and -0.09 (-0.12, -0.06; p < or = 0.001) for loratadine. Strong baseline correlations (R > 0.70; p < 0.001) of NSS and two of its individual symptoms with the sleep domain of the validated Rhinoconjunctivitis Quality of Life Questionnaire support the validity and importance of measuring nighttime morbidity in SAR. Furthermore, a clinically important benefit of montelukast on the nighttime impact of SAR was shown using an analysis anchored on the Patient's Global Evaluation. CONCLUSION: These data underscore the importance of nighttime problems in patients with SAR and the need to treat nighttime symptoms. In these studies, montelukast significantly improved the NSS, a clinically relevant and valid measure in patients with SAR.

Protective effect of montelukast on lower and upper respiratory tract responses to short-term cat allergen exposure.

BACKGROUND: Challenge with short-term exposure to airborne cat allergen in sensitized patients produces pulmonary function changes and rhinitis symptoms. OBJECTIVE: To determine the benefit of montelukast, 10 mg, for patients with concomitant asthma and allergic rhinitis as demonstrated by protection against both lower and upper airway responses to cat allergen challenge. METHODS: This randomized, crossover study treated patients with montelukast vs placebo during two 2-week, double-blind treatment periods, separated by a 1-week washout period. After each treatment period, patients underwent a 60-minute or less exposure to high levels of airborne cat allergen. Lower and upper airway responses were measured by spirometry and symptom scores. RESULTS: Of 52 patients with data from both treatment arms, 79% of patients taking montelukast and 67% taking placebo were exposed to the full 60-minute allergen challenge. Montelukast provided significant (P < or = .001) protection against allergen challenge in the lower airway coprimary end point of area under the curve during challenge (AUC0-60min) for percentage decrease in forced expiratory volume in 1 second: mean of 10.5% per hour and 14.7% per hour for montelukast and placebo, respectively. Although the effect on the overall nasal symptoms score (NSS) coprimary end point of AUC0-60min was not statistically significance (P = .12), nasal congestion during the challenge and NSS during recovery showed statistically significant (P = .048) protection by montelukast. Additional analyses of simultaneous lower and upper airway responses showed that more patients taking montelukast (22, 43%) vs placebo (13, 26%) were protected from both asthma and rhinitis (P = .02), with an odds ratio of 2.24 (95% CI, 1.16-4.32) in favor of montelukast. CONCLUSIONS: Montelukast has a protective effect against both lower and upper airway responses during exposure to high levels of cat allergen.

Montelukast for treating fall allergic rhinitis: effect of pollen exposure in 3 studies.

BACKGROUND: Montelukast, a potent leukotriene receptor antagonist, is an effective therapy for symptoms of seasonal allergic rhinitis, a disease governed by patients' individual sensitivity and exposure to relevant allergens. OBJECTIVE: To evaluate the relationship of montelukast treatment effect vs pollen exposure in studies conducted during 3 consecutive fall allergy seasons. METHOD: A combined analysis of these multicenter, randomized, double-blind, parallel-group studies was performed; 1 of the 3 studies is presented for the first time in this article. After a placebo run-in period, 1,862 symptomatic patients were randomly assigned to receive either a 10-mg montelukast tablet (n = 929) or placebo (n = 933) once daily for 2 weeks. Pollen exposure was summarized by mean daily weed pollen count. The interaction between treatment effect and pollen exposure was evaluated on the primary efficacy endpoint and daytime nasal symptom score, as rated by patients; also evaluated was the influence of the timing of the 2-week treatment period relative to the peak of the weed pollen season. RESULTS: Montelukast significantly improved daytime nasal symptoms score and individual scores of congestion, rhinorrhea, itching, and sneezing compared with placebo. There was a significant interaction (P < .043) between treatment effect and weed pollen exposure; a larger treatment effect was noted in patients exposed to higher pollen counts. An interaction between treatment effect and timing of treatment in relation to peak pollen season was suggested. CONCLUSIONS: Montelukast significantly improved daytime nasal symptoms score in patients with seasonal allergic rhinitis, and the effect was greater in patients exposed to higher pollen levels.

Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis.

BACKGROUND: Symptoms of allergic rhinitis are mediated in part by cysteinyl leukotrienes. OBJECTIVE: To evaluate the clinical benefit of montelukast, a cysteinyl leukotriene receptor antagonist, administered once daily for treating seasonal allergic rhinitis. METHODS: This multicenter, randomized, double-blind, placebo- and active-controlled study enrolled 1,214 healthy, nonsmoking outpatients aged 15 to 85 years with spring allergic rhinitis, positive skin test to a spring allergen, and predefined daytime nasal symptoms. After a 3- to 5-day placebo run-in period, patients were randomly assigned to treatment with montelukast 10 mg (n = 522), loratadine 10 mg (n = 171), or placebo (n = 521) once daily at bedtime for 2 weeks. During the run-in and treatment periods, symptoms were evaluated in a daily diary using a 0 (best) to 3 (worst) scale. RESULTS: Baseline characteristics of randomized patients were clinically similar in the three treatment groups. Montelukast was significantly more effective than placebo (P = 0.003) in improving the daytime nasal symptoms score (difference in least square means, -0.09; 95% confidence interval, -0.16, -0.03) averaged over 2 weeks of therapy. The treatment effect of montelukast was significantly greater (P < 0.05), relative to placebo, for all secondary endpoints, including nighttime symptoms and daytime eye symptoms, patient and physician global evaluations of allergic rhinitis, and rhinoconjunctivitis quality of life. Loratadine, which served as a positive control, was significantly more effective than placebo for most endpoints, validating the study results. Both montelukast and loratadine were well tolerated. CONCLUSION: Therapy with montelukast significantly improves assessments of symptom severity as well as quality-of-life parameters for patients with seasonal allergic rhinitis.

A randomized controlled trial of intravenous montelukast in acute asthma.

Many patients with acute asthma do not respond adequately to currently accepted therapy, including oxygen, beta-agonists, and corticosteroids. Leukotriene receptor antagonists such as montelukast have demonstrated efficacy in chronic asthma, but their efficacy in acute asthma is unknown. In this randomized, double-blind, parallel-group pilot study, adults with moderate to severe acute asthma received standard therapy plus either intravenous montelukast (7 or 14 mg) or matching placebo. A total of 201 patients were randomized, and 194 had complete data available for analysis. There was no difference in FEV1 response between the 7- and 14-mg montelukast groups. Montelukast improved FEV1 over the first 20 minutes after intravenous administration (mean percentage change from prerandomization baseline, 14.8% versus 3.6% for the pooled montelukast and placebo treatment groups, respectively; p = 0.007). This benefit was observed at 10 minutes and over 2 hours after intravenous therapy. Patients treated with montelukast tended to receive less beta-agonists and have fewer treatment failures than patients receiving placebo. The tolerability profile for montelukast was similar to that observed for placebo, and no unexpected adverse experiences were observed. We conclude that intravenous montelukast in addition to standard therapy causes rapid benefit and is well tolerated in adults with acute asthma.