Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group.

OBJECTIVES: To determine the clinical effect of oral montelukast sodium, a leukotriene receptor antagonist, in asthmatic patients aged 15 years or more. DESIGN: Randomized, multicenter, double-blind, placebo-controlled, parallel-group study. A 2-week, single-blind, placebo run-in period was followed by a 12-week, double-blind treatment period (montelukast sodium, 10 mg, or matching placebo, once daily at bedtime) and a 3-week, double-blind, washout period. SETTING/PATIENTS: Fifty clinical centers randomly allocated 681 patients with chronic, stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50% to 85% of the predicted value, at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled beta-agonist administration, a minimal predefined level of daytime asthma symptoms, and inhaled beta-agonist use. Twenty-three percent of the patients used concomitant inhaled corticosteroids. PRIMARY END POINTS: Forced expiratory volume in 1 second and daytime asthma symptoms. RESULTS: Montelukast improved airway obstruction (forced expiratory volume in 1 second, morning and evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, "as-needed" beta-agonist use, nocturnal awakenings) (P<.001 compared with placebo). Montelukast provided near-maximal effect in these end points within the first day of treatment. Tolerance and rebound worsening of asthma did not occur. Montelukast improved outcome end points, including asthma exacerbations, asthma control days (P<.001 compared with placebo), and decreased peripheral blood eosinophil counts (P<.001 compared with placebo). The incidence of adverse events and discontinuations from therapy were similar in the montelukast and placebo groups. CONCLUSIONS: Montelukast, compared with placebo, significantly improved asthma control during a 12-week treatment period. Montelukast was generally well tolerated, with an adverse event profile comparable with that of placebo.

The gastrin-receptor antagonist L-365,260 inhibits stimulated acid secretion in humans.

We investigated the effect of a novel gastrin-cholecystokinin-B receptor antagonist, L-365,260 [(3R)-3(N'-3-methylphenyl)ureido)-1,3-dihydro-5-phenyl- 2H-1,4-benzodiazepin-2-one], on gastric acid secretion in humans. In a double-blind, four-period crossover study, eight subjects received single oral doses of placebo or of 2.5, 10, or 50 mg L-365,260, followed by an intravenous infusion of pentagastrin at doses of 0.05, 0.4, and 2 micrograms/kg/hr for successive 30-minute periods. L-365,260 caused a dose-dependent inhibition of pentagastrin-stimulated gastric acid secretion. A single oral dose of 50 mg L-365,260 produced 50% inhibition of the gastric acid output response to pentagastrin (0.4 micrograms/kg/hr) when the mean (+/- SD) plasma L-365,260 concentration was 502 +/- 108 ng/ml. Plasma L-365,260 concentrations (all doses combined) and the inhibition of gastric acid output were correlated with a correlation coefficient of r = 0.45 (p < 0.05). Single oral doses of L-365,260 up to 50 mg did not inhibit basal gastric acid output or alter plasma gastrin concentrations. L-365,260 was well tolerated at oral doses up to 50 mg. These findings show that L-365,260 is an orally active antagonist at gastrin-cholecystokinin-B receptors in humans.

Blockade of leukotriene production by a single oral dose of MK-0591 in active ulcerative colitis.

BACKGROUND: 5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK-0591 (3-(1((4-chlorophenyl)methyl)-3((1,1-dimethyl-ethyl)thio)-5(quinolin+ ++-2ylmethyl-oxy)-1H-indol-2yl)-2,2-dimethyl-propanoate) exerts its effect by binding to the 5-lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5-lipoxygenase. METHODS: Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in rectal dialysis fluid, ex vivo biosynthesis of LTB4 in whole blood, and urinary excretion of leukotriene E4 (LTE4) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo. RESULTS: The mean LTB4 concentration in rectal dialysis fluid was lowered after MK-0591 by > 90% (p < 0.05) from 4 to 8 hours, with a maximum inhibition of 97.5% +/- 3.4% (mean +/- SD) at 20 to 24 hours after dosing, whereas PGE2 was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB4 (p < 0.01), with a maximum inhibition of 96.4% +/- 2.1% at 4 hours after dosing. Urinary excretion of LTE4 was reduced by more than 85% (p < 0.001) from 4 to 48 hours. No adverse events were observed. CONCLUSION: These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemic leukotriene production and LTB4 formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess the clinical efficacy of this novel 5-lipoxygenase-activating protein inhibitor seem to be worthwhile.

Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor.

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.

Pharmacodynamics and dose-response relationship of famotidine: a double-blind randomized placebo-controlled trial.

The dose-response relationship of oral famotidine at doses up to 10 mg was evaluated in 10 healthy male subjects to assess the extent and duration of inhibition of meal-stimulated intragastric acid secretion. Each subject received single oral administrations of famotidine 0.5, 2.5, 5.0, and 10.0 mg and placebo in a double-blind, randomized, cross-over fashion. Intragastric pH was measured every 4 seconds for 24 hours and expressed as the mean pH for each 10-minute interval. Standard high-protein meals were provided 1 hour before each dose of study drug and at 3 and 9 hours postdose. The mean intragastric pH was significantly higher after famotidine doses 2.5, 5.0, and 10.0 mg than after placebo at times 2.5 to 3.0, 1.8 to 3.2, and 1.7 to 4.2 hours postdose, respectively. There were no significant differences in mean pH seen between famotidine 0.5 mg versus placebo. The range of the pH means between 1.7 and 3.2 hours postdose was placebo (1.0 to 1.3), famotidine 0.5 mg (1.1 to 1.4), 2.5 mg (1.4 to 1.7), 5.0 mg (1.7 to 2.1), and 10.0 mg (2.0 to 2.3). There was a statistically significant linear dose-response relationship between famotidine dose and intragastric pH between 1.7 and 3.8 hours and from 6.3 to 8.7 hours after ingestion.

Lovastatin does not affect oral glucose tolerance in hypercholesterolemic patients.

In 15 non-diabetic Type II hypercholesterolemic patients, the effect of 80 mg lovastatin daily on oral glucose tolerance was investigated. Using a randomized, double-blind, two-panel, parallel design, patients on a low cholesterol diet received lovastatin (n = 7) or placebo (n = 8) for 6 weeks. After 6 weeks of treatment, patients receiving lovastatin had a significant reduction in total cholesterol (30%), LDL-cholesterol (36%), and triglycerides (26%). Time courses of plasma glucose and serum insulin changes from baseline after the oral glucose tolerance test were evaluated by AUC. No statistically significant differences were observed in the AUC of changes from baseline between treatment groups or within either treatment group at prestudy, 6 weeks, and poststudy. No patient had a clinically important laboratory or clinical drug-related adverse effect during the study. This study demonstrated that short-term administration of 80 mg lovastatin daily effectively lowers cholesterol without having adverse effects on oral glucose tolerance.

Analysis of montelukast in mild persistent asthmatic patients with near-normal lung function.

Few studies have specifically evaluated controller therapy in patients with mild persistent asthma. We used a subgroup analysis to investigate the effects of montelukast, a potent cysteinyl leukotriene receptor antagonist, on adult patients on the milder end of the asthma severity spectrum. We have identified seven double-blind, randomized, placebo-controlled studies of adult patients with mild-to-moderate chronic asthma in which montelukast was investigated. Subsets of patients with baseline forced expiratory volume in 1 sec (FEV1) > 80% and > 75% predicted or further restricted by less than daily rescue beta-agonist use were included as four cohorts (A, B, C, D), and efficacy measures, including change in FEV1 rescue-free days, beta-agonist use, nocturnal awakenings and blood eosinophil counts were evaluated. Cohorts A to D comprised 21%, 8%, 11%, and 4%, respectively, of patients from these studies. Mean pretreatment FEV1 ranged from 81% to 84% predicted and daily beta-agonist use from 2.4 to 4.5 puffs day(-1) in the four cohorts. Pooled results demonstrated a treatment effect for montelukast over placebo in all cohorts, for all endpoints. There was a significant improvement in FEV1 in montelukast-treated patients (7-8% over baseline) compared with placebo (1-4% over baseline, between-group difference P < or = 0.02) for all cohorts. Similarly, the percentage of rescue-free days increased substantially more with montelukast (22-30%) than with placebo (8-13%). This subgroup analysis indicates that montelukast produced improvements in parameters of asthma control in patients with milder persistent asthma that should be confirmed in additional prospective trials.

Correlation of airway obstruction and patient-reported endpoints in clinical studies.

To establish the correlation among asthma efficacy parameters over a long period, data from over 1,500 patients in two one-year asthma clinical trials with montelukast, a Cys-LT1 antagonist, were analysed. Airway obstruction measurements, forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF), were measured at clinic visits. Patients recorded daytime symptom score, "as-needed" beta-agonist use, and PEF on a daily basis. Relationships among these parameters at baseline and during the one-year treatment period were established by correlation analyses. Multiple correlations between the airway obstruction (FEV1 and PEF) and patient-reported measurements were evaluated by canonical correlation analysis. Pairwise correlations of the efficacy parameters over a one-year time period were stable. Canonical correlation between the airway obstruction and patient-reported asthma efficacy endpoints was low, indicating that each category of endpoints measures a distinctively different aspect of the disease. It appears that at least one endpoint from each category should be used in asthma clinical studies.

Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study.

BACKGROUND: Previous studies in patients with osteoarthritis have suggested that the selective cyclooxygenase (COX)-2 inhibitor rofecoxib results in less gastrointestinal damage than non-selective non-steroidal antiinflammatory drugs (NSAIDs). This study compared the incidence of endoscopically detected gastroduodenal ulcers in rheumatoid arthritis patients treated with rofecoxib or a non-selective NSAID. METHODS: In this multicentre, randomised, double blind, 12 week study, patients with rheumatoid arthritis were allocated to rofecoxib 50 mg once daily (n=219), naproxen 500 mg twice daily (n=220), or placebo (n=221). Endoscopy was performed at baseline and at six and 12 weeks. Lifetable analysis and log rank tests were used to analyse the incidence of gastroduodenal ulcers > or =3 mm. Gastric or duodenal ulcers > or =5 mm and erosions were also evaluated as secondary end points. Tolerability was assessed by adverse events. RESULTS: The cumulative incidence of ulcers > or =3 mm at 12 weeks was significantly higher in patients on naproxen (25.5%) than in patients receiving rofecoxib (6.8%; difference 18.7% (95% confidence interval (CI) 11.7%, 25.7%); p<0.001) or placebo (2.9%; difference 22.6% (95% CI 16.1%, 29.1%); p<0.001). The difference between rofecoxib (6.8%) and placebo (2.9%) did not reach statistical significance (p=0.066). Results were similar for ulcers > or =5 mm and for mean changes from baseline in the number of gastroduodenal erosions. The overall incidence of clinical adverse events was similar among treatment groups (61% of patients on placebo, 62% in patients on rofecoxib, and 66% in patients on naproxen). CONCLUSIONS: Rofecoxib 50 mg daily (twice the dose recommended for this patient population) resulted in a lower incidence of endoscopically detected gastroduodenal ulcers and erosions than treatment with naproxen 500 mg twice daily.

Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged > or = 6 years.

OBJECTIVE: Montelukast is a leukotriene receptor antagonist administered orally once daily for treatment of chronic asthma in adults and children. A comprehensive analysis of safety data from double-blind, randomized, placebo-controlled trials with montelukast has not been previously reported. PATIENTS AND METHODS: A pooled analysis of safety data from 11 multicentre, randomized, controlled montelukast Phase IIb and III trials and five long-term extension studies was performed. A total of 3386 adult patients (aged 15-85 years) and 336 paediatric patients (aged 6-14 years) were enrolled in the trials; 2031 adults received montelukast for up to 4.1 years, and 257 children received montelukast for up to 1.8 years. Summary statistics comparing incidences of adverse events among treatment groups were calculated. RESULTS: The overall incidence of clinical and laboratory adverse events among montelukast-treated patients, both adult and paediatric, was similar to that among patients receiving placebo. There were no clinically relevant differences in individual adverse events, including infectious upper respiratory conditions and transaminase elevations, between montelukast and placebo groups. Discontinuations due to adverse events occurred with similar frequencies during placebo, montelukast and inhaled beclomethasone therapy. No dose-related adverse effects of montelukast were observed in adults treated with dosages as high as 200 mg per day (20 times the recommended dose) for 5 months. This tolerability profile montelukast observed in clinical trials has been generally reflected in the post-marketing safety experience seen to date. CONCLUSIONS: These data indicate a tolerability profile for montelukast similar to placebo during both short-term and long-term administration, even at doses substantially higher than the recommended clinical dose of 10 mg once daily for adults and 5 mg once daily for children aged 6-14 years.

A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. Montelukast Asthma Study Group.

BACKGROUND: The cysteinyl leukotrienes are important mediators of bronchial asthma. The clinical effect of montelukast, a potent cysteinyl leukotriene-receptor antagonist, was investigated in a randomized, placebo-controlled, multicenter, parallel-group, dose-ranging study. METHODS: After a 3-week, single-blind, placebo run-in period, 343 asthmatic patients (FEV1 40% to 80% of the predicted value with an improvement in FEV1 of at least 15% [absolute value] after receiving inhaled beta-agonists on at least two occasions) were randomly assigned to one of six treatment groups: placebo; 10, 100, or 200 mg once daily montelukast in the evening; or 10 or 50 mg twice daily montelukast for a 6-week, double-blind treatment period followed by a 1-week placebo washout period. All patients used inhaled, short-acting beta-agonists as needed. RESULTS: All montelukast doses caused similar and significant differences compared with placebo in asthma control endpoints. The least-square mean difference between pooled montelukast groups and placebo in the percentage change from baseline in morning FEV1 (10.30%; 95% CI: 5.56 to 15.04), as-needed beta-agonist use (-0.98 puffs; 95% CI: -1.53 to -0.44), morning peak expiratory flow rate (18.80 L/min; 95% CI: 8.62 to 28.98), physicians' and patients' global evaluations, and asthma-specific quality-of-life scores were all significant (p < or = 0.050). The incidence of adverse experiences was not dose related and was similar between placebo and montelukast treatment. CONCLUSION: Montelukast caused a significant improvement in chronic asthma at an oral, once daily evening dose as low as 10 mg.

Acute bronchodilation with an intravenously administered leukotriene D4 antagonist, MK-679.

Descriptive studies suggest an association between the release of the cysteinyl leukotrienes and clinical asthma. To help clarify this association, we tested the hypothesis that an intravenous infusion of a potent and specific investigational LTD4 receptor antagonist, MK-679, would cause rapid bronchodilation. In a three-period, randomized, double-blind, crossover study, single doses of MK-679, 125 and 500 mg, and placebo were given intravenously by bolus infusion to nine patients with moderate, stable asthma (FEV1 40 to 80% predicted) on individual study days separated by a week. Spirometry was preformed predose and at intervals for as long as 8 h postdosing; blood samples for MK-679 concentrations were drawn over this time. Fifteen minutes after the end of infusion, the FEV1 percent change from baseline increased a mean of 15.8 +/- 15.7 and 7.8 +/- 11.6% with the 500- and 125-mg doses, respectively, compared with a mean decrease of 2.6 +/- 6.2% with placebo (p = 0.01, overall; p = 0.003, 500 mg versus placebo). The mean end-of-infusion MK-679 plasma concentrations were 86.2 +/- 13.9 and 19.9 +/- 2.7 micrograms/ml for the 500- and 125-mg doses, respectively. MK-679 was well-tolerated, with no significant adverse experiences observed. We conclude that a single, intravenously administered, bolus infusion of MK-679 causes bronchodilation in patients with moderate, stable asthma.

Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses.

To elucidate the role of leukotrienes (LT) in allergic asthma in humans the effect of MK-886, an LT biosynthesis inhibitor, was evaluated on antigen-induced early (EAR) and late (LAR) asthmatic reactions and bronchial responsiveness to histamine. Eight atopic men participated in a two-part, double-blind, placebo-controlled, crossover trial. MK-886 was administered in two oral doses of 500 mg and 250 mg, 1 h before and 2 h after allergen inhalation, respectively. Biochemical effects of MK-886 were evaluated by the inhibition of urinary LTE4 excretion and calcium ionophore-stimulated LTB4 biosynthesis in whole blood ex vivo. MK-886 significantly inhibited the EAR by 58.4% (AUC0-3 h) and the LAR by 43.6% (AUC3-7 h) when compared with placebo (p < 0.01). There was no difference in PC20 histamine 30 h post allergen challenge between MK-886 and placebo (0.33 and 0.27 doubling doses, p > 0.1). MK-886 inhibited calcium ionophore-stimulated LTB4 production in whole blood (54.2 +/- 25.6%) for up to 6 h post allergen challenge. LTE4 excretion in urine was inhibited by 51.5% during the EAR by as much as 80% during the LAR. This indicates that LT play a role in allergen-induced asthmatic reactions in humans in vivo and that LT synthesis inhibitors such as MK-886 should be further explored for the treatment of asthma.

A placebo and active comparator-controlled trial of rofecoxib for the treatment of rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and tolerability of rofecoxib 25 mg and 50 mg once daily versus placebo and naproxen 500 mg twice daily in patients with RA. METHODS: Eligible patients were randomized (double-blind) to placebo (n = 289), rofecoxib 25 mg (n = 306), 50 mg (n = 286) once daily, or naproxen (n = 142) for 12 weeks. Efficacy assessments included the ACR core set, with prespecified primary endpoints: patient and investigator global assessments of disease activity, tender and swollen joint counts. Investigator-reported adverse experiences, routine laboratory and vital sign measurements were monitored. RESULTS: Rofecoxib 25 mg, 50 mg, and naproxen provided similar treatment effects, significantly different from placebo, consistent with improvement, for all primary endpoints. Effects were evident at the earliest assessment (week 2) and sustained for 12 weeks. All treatments were generally well-tolerated. CONCLUSIONS: Rofecoxib 25 mg once daily had similar efficacy to naproxen 500 mg twice daily (a standard dose). No additional benefit was seen with 50 mg rofecoxib.

Effect of montelukast on single-dose theophylline pharmacokinetics.

The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist in development for treatment of asthma, on single-dose theophylline plasma concentrations was studied in three separate clinical trials. Montelukast was evaluated at 10 mg once daily (the clinical dosage), 200 mg once daily, and 600 mg (200 mg three times daily). At the clinical dosage, montelukast did not change single-dose theophylline plasma concentration in a clinically important manner. The geometric mean ratios for theophylline area under the plasma concentration versus time curve (AUC0-->infinity ) (0.92) and maximal plasma concentration (Cmax ) (1.04) were well within the predefined and generally accepted bioequivalence range of 0.80 and 1.25. Montelukast decreased theophylline Cmax by 12% and 10%, AUC0-->infinity by 43% and 44%, and elimination half-time by 44% and 39% at 200 mg/d (oral and intravenous, respectively), and at 600 mg/d, montelukast decreased theophylline Cmax by 25%, AUC0-->infinity by 66%, and elimination half-time by 63%. These results show that montelukast at the clinical dosage did not change theophylline pharmacokinetics in a clinically important manner, but at 20- to 60-fold higher dosages, montelukast significantly reduced the theophylline pharmacokinetics parameters; an apparent dosage dependence is suggested.