Efficacy of desloratadine in intermittent allergic rhinitis: a GA(2)LEN study.

BACKGROUND: The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines proposed a classification for allergic rhinitis based on the duration of symptoms (intermittent, persistent) rather than on the time of allergen exposure (seasonal, perennial). There is no placebo-controlled, randomized clinical trial on intermittent allergic rhinitis (IAR) to date. Desloratadine (DL) is recommended for the first-line treatment of seasonal and perennial allergic rhinitis. OBJECTIVES: To assess the efficacy and safety of DL in subjects with IAR based on the ARIA classification. METHODS: Patients over 12 years of age with IAR were assessed over 15 days of treatment with DL 5 mg once daily (n = 276) or placebo (n = 271). The primary endpoint was the AM/PM reflective total 5 symptom score (T5SS). Secondary endpoints included AM/PM instantaneous T5SS and individual symptoms, therapeutic response, symptom severity by visual analogue scale, and quality-of-life. RESULTS: The mean reduction of AM/PM reflective T5SS was significantly greater with DL than with placebo over 15 days (-3.01 vs-2.13, P < 0.001) and on each individual day (P < 0.05). Mean AM instantaneous T5SS was reduced significantly with DL compared to placebo as early as day 2 (-1.84 vs-0.89; P < 0.001). The therapeutic response and improvement in quality-of-life were significantly greater with DL than with placebo (P < 0.001 for each). The frequency of treatment-related adverse events was low and similar between DL (7.2%) and placebo (7.0%). CONCLUSIONS: This is the first large trial to show that treatment can be effective in IAR. Desloratadine was effective and safe.

Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray. The Nasonex Sinusitis Group.

BACKGROUND: Intranasal glucocorticoids are effective in the treatment of allergic rhinitis. Their effectiveness as an anti-inflammatory adjunct in the treatment of acute recurrent sinusitis has not been adequately established in a controlled clinical study. OBJECTIVE: The purpose of this study was to test the hypothesis that intranasal corticosteroid treatment produces additional relief in the treatment of acute sinusitis with oral antibiotics. METHODS: Patients who were 12 years old and older with a history of recurrent sinusitis were treated while experiencing a new episode of acute sinusitis, which was diagnosed by symptoms and confirmed by computed tomography scan of the paranasal sinuses. Patients were treated for 21 days with amoxicillin clavulanate potassium and randomized to receive concurrent mometasone furoate nasal spray (MFNS; Nasonex [400 microg, twice daily]; n = 200 patients) or placebo spray (twice daily; n = 207 patients). Symptom scores for headache, facial pain, congestion, purulent rhinorrhea, postnasal drip, and cough were recorded at baseline and throughout treatment. RESULTS: Baseline symptom scores showed a moderate level of symptom severity comparable in both groups. Patient-recorded twice daily symptom scores showed that adjunctive treatment with MFNS caused a significantly greater decrease in total symptom score (primary efficacy variable) and in individual scores of inflammatory symptoms associated with the obstruction process (headache, congestion, and facial pain) compared with placebo. Symptoms associated with the secretory processes were improved to a lesser degree. Therapy-related local adverse events were not significantly different between groups. CONCLUSION: The addition of intranasal corticosteroid, MFNS 400 microg twice daily, to antibiotics significantly reduces symptoms of acute sinusitis compared with antibiotic treatment alone.

The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children aged 2 to 5 years.

OBJECTIVE: We assessed the pharmacokinetics and tolerability of 5 mg loratadine syrup (1 mg/mL) in children aged 2 to 5 years. METHODS: Two studies were undertaken. A single-dose, open-label bioavailability study was performed to characterize the pharmacokinetic profiles of loratadine and its metabolite desloratadine. Plasma concentrations of loratadine and desloratadine were determined at 0, 1, 2, 4, 8, 12, 24, 48, and 72 hours after a single administration of 5 mg loratadine syrup to 18 healthy children (11 male, 7 female; 12 black, 5 white, 1 other; mean age +/- SD, 3.8 +/- 1.1 years; mean weight +/- SD, 17.4 +/- 4.4 kg). In addition, a randomized, double-blind, placebo-controlled, parallel-group study was performed to assess the tolerability of 5 mg loratadine syrup after multiple doses. Loratadine (n = 60) or placebo (n = 61) was given once daily for 15 days to children with a history of allergic rhinitis or chronic idiopathic urticaria. In the loratadine group, 27 boys and 33 girls (52 white, 8 black) were enrolled, with a mean age +/- SD of 3.67 +/- 1.13 years and a mean weight +/- SD of 17.2 +/- 3.8 kg. In the placebo group, 27 boys and 34 girls (53 white, 7 black, 1 Asian) were enrolled, with a mean age +/- SD of 3.52 +/- 1.12 years and a mean weight +/- SD of 17.3 +/- 2.9 kg. Tolerability was assessed based on electrocardiographic results, occurrence of adverse events, changes in vital signs, and results of laboratory tests and physical examinations. RESULTS: The peak plasma concentrations of loratadine and desloratadine were 7.78 and 5.09 ng/mL, respectively, observed 1.17 and 2.33 hours after administration of loratadine; the areas under the plasma concentration-time curve to the last quantifiable time point for loratadine and desloratadine were 16.7 and 87.2 ng x h/mL, respectively. Single and multiple doses were well tolerated, with no adverse events occurring with greater frequency after multiple doses of loratadine than after placebo. Electrocardiographic parameters were not altered by loratadine compared with placebo. There were no clinically meaningful changes in other tolerability assessments. CONCLUSION: Loratadine was well tolerated in this small, selected group of children aged 2 to 5 years at a dose providing exposure similar to that with the adult dose (ie, 10 mg once daily).

Comparative efficacy and safety of once-daily versus twice-daily loratadine-pseudoephedrine combinations versus placebo in seasonal allergic rhinitis.

The objective of this study was to compare the efficacy and safety of Claritin-D 24 Hour (once daily) with that of Claritin-D 12 Hour (twice daily) and placebo in the treatment of patients with seasonal allergic rhinitis (SAR). In this double-blind, placebo-controlled, multicenter study, 469 patients with moderate-to-severe SAR symptoms were treated for 2 weeks with one of the following: Claritin-D 24 Hour (a combination tablet formulation of loratadine 10 mg in the coating and pseudoephedrine sulfate 240 mg in an extended-release core), Claritin-D 12 Hour (a combination tablet formulation of loratadine 5 mg in the tablet coating and 120 mg pseudoephedrine sulfate, 60 mg in the coating and 60 mg in the core), or placebo. Claritin-D 24 Hour and Claritin-D 12 Hour were consistently superior to placebo (P < 0.01) in reducing total, nasal, and nonnasal symptom scores. Patients in the Claritin-D 24 Hour and Claritin-D 12 Hour groups also had significantly greater (P

A comparison of double-strength beclomethasone dipropionate (84 microg) MDI with beclomethasone dipropionate (42 microg) MDI in the treatment of asthma.

STUDY OBJECTIVE: To compare the efficacy and safety of a double-strength formulation of beclomethasone dipropionate (BDP 84) metered-dose inhaler (MDI) with that of beclomethasone dipropionate (BDP 42) MDI in the treatment of chronic asthma. DESIGN: A 28-day, randomized, double-blind, double-dummy, placebo-controlled, multicenter study. SETTING: Outpatient. PATIENTS: A total of 423 patients aged 12 to 65 years (mean range, 34 to 36 years) with moderate asthma (FEV1, 50 to 80% of predicted) who required long-term inhaled corticosteroids were enrolled. INTERVENTIONS: Patients were randomized to receive BDP 84, two oral inhalations bid (336 microg/d), BDP 42, four oral inhalations bid (336 microg/d), or placebo. A fourth treatment arm administering BDP 84, eight oral inhalations bid (HD BDP 84; 1,344 microg/d) was also included to determine whether a dose-response relationship could be demonstrated. MEASUREMENTS: Spirometry, clinical observations. RESULTS: The three active treatments were significantly more effective (p < or = 0.01) than placebo at all time points in improving FEV1, the primary efficacy parameter; BDP 42 and BDP 84 were comparable to each other at every time point. Secondary pulmonary function tests (FVC, forced expiratory flow at 25 to 75% of FVC, and peak expiratory flow rate) showed similar results. All three active treatments were well tolerated. A dose response between 336 microg/d and 1,344 microg/d was demonstrated. CONCLUSION: In this well-controlled 28-day study, BDP 42 and BDP 84 were shown to be comparable in efficacy and safety on a microgram-for-microgram basis.

Double-strength beclomethasone dipropionate (84 micrograms/spray) aqueous nasal spray in the treatment of seasonal allergic rhinitis.

BACKGROUND: The use of intranasally administered corticosteroid sprays is an established treatment option for seasonal allergic rhinitis. METHODS: In this double-blind, placebo-controlled, multicenter study, 438 patients with moderate to severe symptoms of seasonal allergic rhinitis were treated for 4 weeks with double-strength beclomethasone dipropionate (BDP) aqueous nasal spray (84 micrograms/spray: BDP-ds), once daily; regular-strength BDP (42 micrograms/spray: BDP-rs), twice daily; high-strength BDP (336 micrograms/spray: BDP-hs), once daily; or placebo. BDP-hs was included as a safety comparison group. All treatments were given as two sprays per nostril. RESULTS: Physician-rated nasal symptom scores were significantly improved in all three active treatment groups compared with those of the placebo group within the initial 3 days of treatment. Improvement was maintained throughout the 4-week treatment period. BDP-ds and BDP-rs were equivalent at all time points. The BDP-ds, BDP-rs, and BDP-hs groups had greater numbers of patients with a good or excellent therapeutic response at end point than the placebo group. All treatments were well-tolerated, and no unexpected adverse events were reported. No effects on laboratory evaluations or vital signs were evident for any treatment group. CONCLUSIONS: The results of this study show that BDP-ds given once a day and BDP-rs given twice a day in the same total daily dose are comparably safe and effective in the treatment of patients with seasonal allergic rhinitis.

Extended-release albuterol in the treatment of 6- to 12-year-old asthmatic children.

BACKGROUND: Albuterol sulfate, in the syrup and tablet form for oral administration, has been an effective treatment for adults and children with bronchial asthma. Extended-release albuterol sulfate tablets (Proventil Repetabs, Schering Corp.) provide a convenient, twice-daily dosing regimen, but are indicated only for patients > or = 12 years of age. OBJECTIVE: This study was undertaken to determine whether patients 6 to 12 years of age could be effectively and safely treated with extended-release albuterol tablets. METHODS: This was a randomized, double-blind, placebo-controlled, parallel group study of 157 patients in five centers. Patients were randomized to 4 weeks' treatment with extended-release albuterol tablets, 4 mg twice daily (q 12h), increasing up to 12 mg q 12h, or placebo. Efficacy was evaluated based on pulmonary function tests (PFTs), physician and patient evaluations, and data collected from patients' diaries on PEFR, asthma symptoms, number of nighttime awakenings, and number of tablets taken. The primary efficacy parameter was area under the curve (AUC) for FEV1, evaluated for 8 to 12 hours post-dosing. Safety was evaluated based on vital signs, electrocardiograms, and adverse events. RESULTS: Mean AUCs for FEV1 were significantly greater in the albuterol group at days 1 and 8 (P < or = .03). The albuterol group showed consistently lower severity scores for asthma symptoms. Physicians' and patients' global evaluations favored the albuterol group over the placebo group. No serious, treatment-related adverse events were reported. There were no clinically meaningful changes from baseline in either treatment group for vital signs or electrocardiograms. CONCLUSIONS: Extended-release albuterol tablets (4 mg), administered to children 6 to 12 years old in divided doses of up to 24 mg/day, improved pulmonary function and asthmatic symptoms and were well tolerated.

Conversion from twice- to once-daily extended-release theophylline treatment in patients with reversible airway obstruction.

This multicenter, randomized, investigator-blinded, parallel group study compared the effects of converting patients from a q12h extended-release theophylline preparation (Theo-Dur) to a q24h extended-release product (Uni-Dur). Patients (n = 133) first received open-label Theo-Dur treatment with dosage titrated to achieve peak serum theophylline concentrations of 10-20 micrograms/ml. Patients then were randomized to continue Theo-Dur (n = 64) or to convert to Uni-Dur (n = 60) with peak serum theophylline concentrations maintained in the desired range. Pulmonary function tests were performed during the open-label and blinded periods; patients maintained diaries and performed peak flow measurements before each dose of study treatment. Adverse events were recorded throughout the study. Respiratory status during blinded treatment was rated as the same or improved compared with open-label treatment by > 87% of evaluable patients and physicians, regardless of treatment group. There were no significant differences in mean peak serum theophylline concentrations at baseline, at the final evaluation, or at any point during the study. Few dosage adjustments were necessary (5/52, Uni-Dur; 9/57, Theo-Dur). There were no significant changes in pulmonary function test results or patient diary entries between the open-label and blinded periods. Headache and nausea were the most commonly reported adverse events. In conclusion, converting patients from twice- to once-daily theophylline treatment resulted in no significant changes in any measures of pulmonary function, and there were no significant differences between the groups during the blinded treatment period.

Relative absence of neuropsychological deficit in patients with low grade astrocytomas.

Given the current accuracy and precision of modern brain imaging technology, there is presumed to be little utility in neuropsychological assessment procedures in patients with brain tumors. The primary exposure of many clinical neuropsychologists to patients with brain tumors is during their training, in the form of didactic classroom activities, such as reviewing the brain tumor cases of early investigators in the field. Historically, these brain tumors were the more aggressive and destructive tumors, such as grade III and IV astrocytomas, that could be identified with pre CT and pre MRI technology. With current imaging technology, low grade tumors that might previously have gone undiagnosed for years can be detected and patients followed over time. This series of cases represents documentation of the very unique neuropsychological status of patients with relatively slow growing, infiltrative brain tumors classified as grade II astrocytomas. The potential relevance of neuropsychological assessment for such cases is discussed.

Onset of action of loratadine and placebo and other efficacy variables in patients with seasonal allergic rhinitis.

In a double-blind study, 185 patients with seasonal allergic rhinitis were randomly assigned to receive 10 mg of loratadine or placebo once daily for three days. On day 1 of treatment, the onset of relief of symptoms within 30 minutes of drug administration was reported by 13% of the loratadine-treated patients and by 4% of the placebo patients (P less than 0.05). At two hours after drug administration, 65% of the loratadine-treated patients and 48% of the placebo patients reported symptom relief. On day 3, the loratadine-treated patients reported a significantly greater relief of symptoms, and according to both physician and patient evaluations, the treatment response was significantly superior in the loratadine-treated than in the placebo patients. The incidence of sedation was 2% in the loratadine group and 1% in the placebo group.

Netilmicin sulfate as single-agent therapy for Pseudomonas infections.

In a prospective multicenter clinical trial, 69 patients with Pseudomonas infections were treated with netilmicin sulfate as the only antipseudomonal antibiotic. Clinical resolution or improvement was observed for 81% of the infections, whereas 19% were considered treatment failures. The bacteriologic response, based on follow-up culture results, showed elimination of Pseudomonas from 62% of the infection sites, with persistence in 30%. All isolates were susceptible by disk susceptibility testing (zone greater than or equal to 15 mm), and by microdilution testing in unsupplemented broth. The majority of isolates, however, were resistant in cation supplemented media. The clinical failures could be accounted for by factors other than netilmicin failure. In conclusion, netilmicin appeared effective as treatment for netilmicin-susceptible Pseudomonas infections in nonneutropenic adults. A low incidence of nephrotoxicity (12%) occurred despite careful monitoring of serum levels.

A multicentric study of netilmicin once daily versus thrice daily in patients with appendicitis and other intra-abdominal infections.

This multicentric, randomized, double-blind trial compared the efficacy and safety of netilmicin, 4.5 mg/kg od and 1.5 mg/kg tid, in patients with intra-abdominal infections. Of 114 patients enrolled, 57 patients (mean age 40.3 years) in the od group and 55 (mean age 36.8 years) in the tid group were evaluated for efficacy; 58 and 56 patients in corresponding groups were evaluated for safety. Among those evaluated for efficacy were 12 od-treated and 11 tid-treated patients with documented septicaemia, and 32 and 30 patients of respective groups with polymicrobial infections. Initially, 86 and 81 netilmicin-susceptible causative microorganisms were isolated in corresponding groups. Of these pathogens, 55% in the od group and 62% in the tid group were Escherichia coli. Daily dosage of netilmicin ranged from 3.70 to 4.71 mg/kg (mean 4.50) for the od group and from 3.06 to 4.76 mg/kg (mean 4.46) for the tid group. Duration of netilmicin therapy ranged from six to 13 days (mean 8.7 days) for od-treated patients and from seven to 16 days (mean 8.8 days) for tid-treated patients. Concomitant metronidazole was administered to 41 patients of the od group and 34 of the tid group; one patient in the tid group received clindamycin. Clinical and bacteriological responses were assessed, and peak and trough serum netilmicin levels were measured periodically, during therapy. Laboratory tests, including determinations of serum creatinine and blood urea nitrogen values, were performed throughout the trial. A clinical cure was achieved in 57/57 od-treated patients and 54/55 tid-treated patients; treatment failed in one tid-treated patient (1/55). In od and tid groups, 86/86 and 80/81 netilmicin-susceptible pathogens initially isolated were considered to be eliminated, respectively; one isolate (Esch. coli) persisted in the tid group. Mean peak serum netilmicin concentration in the od group was approximately two-fold greater than that in the tid group; mean trough serum netilmicin concentrations were similar for the two groups. Adverse reactions were limited to mild pain at the site of netilmicin administration in several patients in each treatment group. Netilmicin od and tid (alone or in combination with metronidazole) were similarly efficacious in the treatment of patients with appendicitis and other intra-abdominal infections caused by netilmicin-susceptible pathogens. Both dosage regimens of netilmicin were safe and well tolerated.

Pitfalls in the use of a continuous performance test as a diagnostic tool in attention deficit disorder.

Although automated continuous performance tests (CPT) are gaining popularity as aids to the diagnosis of attention deficit disorder (ADD), little is known of their validity in this context. Our preliminary experience with a commercially available visual CPT indicated that as many as a third of children meeting the DMS-III criteria for ADD may score well enough on this measure to escape detection. We therefore analyzed the results of neuropsychological testing as well as CPT performance in 14 ADD children and six non-ADD children in an effort to determine whether CPT performance might reflect higher level cognitive variables other than attention and/or impulsivity. We found that those ADD children classified as "abnormal" on the basis of the CPT scored significantly below those classified as "normal" on measures of abstract reasoning and logical problem solving, simple verbal reasoning, nonverbal problem solving, and simple arithmetic skills. The non-ADD group contained a high proportion (83%) of subjects with CPT performance outside of the normal range. These data suggest that CPT may yield both false negative and false positive results when used as screening tools for ADD, and we recommend therefore that caution be used in their interpretation.

The go-no-go paradigm in attention deficit disorder.

We administered the go-no-go paradigm to 44 boys with attention deficit disorder (ADD) and 32 control subjects who did not have ADD. This task requires a subject to emit a simple motor response to one cue while inhibiting the response in the presence of another cue. Commission errors suggest impulsivity, and omission errors suggest inattention. ADD subjects made more total errors than did control subjects (p less than 0.03), and more ADD subjects made multiple errors (p less than 0.001). Within the ADD group, the nonhyperactive (ADDnoH) subjects were characterized by a high number of commission errors early, and significant improvement with practice (p less than 0.01). In contrast, the hyperactive ADD subjects (ADD/H) did not differ from control subjects in number of early commission errors, but differed from both control subjects and ADDnoH subjects in their failure to improve with practice. In addition, the incidence of omission errors was highest in the ADD/H group. This paradigm can be easily incorporated into the assessment of children with suspected ADD and provides an objective measure of inattention and impulsivity. Our data provide cognitive support for the empirical distinction between hyperactive and nonhyperactive children with ADD.

Influence of cation supplements on activity of netilmicin against Pseudomonas aeruginosa in vitro and in vivo.

In vitro studies were performed with 74 Pseudomonas aeruginosa isolates which were collected during a multicenter trial. The isolates were obtained from 70 patients who had been treated with netilmicin as the only antipseudomonal antibiotic. Clinically, 83% of the patients were cured or improved, and 64% of the Pseudomonas isolates were eliminated by chemotherapy. The 74 clinical isolates and 38 additional isolates with known mechanisms of aminoglycoside resistance were tested in three separate laboratories by disk diffusion methods and by microdilution tests with three broth media (Mueller-Hinton broth with full, half, and no cation supplements). Isolates that responded to netilmicin therapy and those that failed to respond were all susceptible by the disk test, and most were susceptible by microdilution tests with unsupplemented broth. However, over half of the clinical isolates appeared to be resistant when cations were added to the broth medium. Strains capable of producing enzymes that inactivate netilmicin were resistant by all methods tested. Broth dilution and agar dilution results were most comparable when half of the recommended cation supplements was added to Mueller-Hinton broth. Further consideration should be given to reducing the concentration of cations that are added to Mueller-Hinton broth when netilmicin susceptibility tests are being performed. However, additional studies with other aminoglycosides are needed before appropriate testing conditions can be standardized.

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

Netilmicin in the treatment of Pseudomonas bacteremia.

The effectiveness of netilmicin was evaluated retrospectively in 40 patients with culture-documented bacteremia due to Pseudomonas aeruginosa. Netilmicin was the only antibiotic active in vitro against P aeruginosa that was administered to these patients. In 18 patients, Pseudomonas bacteremia developed in association with a Pseudomonas infection of the urinary tract; in 22 patients, Pseudomonas bacteremia developed from nonurinary or unknown sources. A clinical resolution or improvement was observed in 92% of the evaluable patients, and P aeruginosa was eliminated from the blood of 90% of the patients. The drug had nephrotoxic effects in two patients, but in no patient was there subjective or audiometric evidence of ototoxic effects. Three patients died during therapy. Based on these data, netilmicin is effective, and is associated with a low incidence of toxic effects, in the treatment of patients with Pseudomonas bacteremia.

Netilmicin versus tobramycin in multi-centre studies.

In two prospective, randomized studies conducted in West Germany and involving 80 patients, netilmicin-ticarcillin was compared to tobramycin-ticarcillin in the treatment of serious systemic infections. Both regimens were essentially identical with respect to the clinical and bacteriological results they produced. The netilmicin group developed significantly less nephrotoxicity than the tobramycin group (0% versus 15%, P = 0.03). Ototoxicity also occurred less frequently in the netilmicin-treated patients (3% versus 10%, P = 0.4). In a large collaborative study involving 15 centres, 254 patients were enrolled. Clinical and bacteriological responses were excellent, with netilmicin and tobramycin equally effective, but the incidences of nephrotoxicity and ototoxicity were lower in patients treated with netilmicin than those receiving tobramycin.