Harold B. Kaiser

The Effect of Inhibition of 5-Lipoxygenase by Zileuton in Mild-to-Moderate Asthma

Although intermittent episodic airway narrowing occurs in persons with asthma, the biochemical basis of this obstruction has not been elucidated. Nonetheless, inflammatory cells present in the airways of persons with asthma [1, 2] release various substances that narrow airways. Among these are cysteinyl leukotrienes, which are formed from arachidonic acid in part by the enzyme 5-lipoxygenase [3]. The evidence favoring a role for leukotrienes in asthma is that they are produced by various airway cells including eosinophils and mast cells [4, 5], they are potent bronchoconstrictor agonists [6-8], and they can be recovered from biological fluids during asthma attacks [9-11]. Recently, the salutary effects of specific leukotriene-receptor antagonists or synthesis inhibitors in persons with asthma have suggested that interventions in the 5-lipoxygenase pathway may be of therapeutic use in the treatment of asthma [12-20]. These observations are particularly interesting because of the increasing concerns about asthma therapies such as -agonists and theophylline [21-24] and the known toxicity of long-term steroid use [25, 26]. However, the conclusions about the efficacy of these new drugs in persons with asthma largely derive from studies in laboratory-induced, rather than spontaneously occurring, asthma. Because cases of spontaneously occurring asthma may differ from those of laboratory-induced asthma, in mechanism or in response to therapy, we examined the effects of zileuton (N-1-[benzo(b)thien-2-ylethyl]-N-hydroxyurea), an investigational inhibitor of 5-lipoxygenase [27] currently in phase III trials of efficacy, in persons with asthma. In a double-blind, placebo-controlled trial in patients with mild-to-moderate airflow obstruction, we investigated the effects of inhibition of 5-lipoxygenase with zileuton (Leutrol; Abbott Laboratories, North Chicago, Illinois), during a 4-week period, on airway function, asthma symptoms, and the bronchodilator response to -agonists. We found that a dose of 600 mg four times per day (2.4 g/d), which produces more than 35% inhibition of leukotriene production as indicated by excretion of leukotriene E4 (LTE4) in the urine, had a salutary effect on airway function and asthma symptoms. Methods Patient Selection Patients with mild-to-moderate asthma were recruited at 14 centers, which included university hospitals and private allergy and pulmonary practices. Patients with symptoms that corresponded with the American Thoracic Society definition of asthma [28] were screened. All patients had to have a forced expiratory volume in 1 second (FEV1) of 40% to 75% of predicted value and a 15% or greater increase in FEV1 30 minutes after inhalation of two puffs of albuterol. Additionally, patients were required to be 18 to 65 years old; women of childbearing potential were excluded. Before enrollment in the study, none of the patients had used oral or inhaled steroids or cromolyn sodium for 4 weeks. Beta-blockers, calcium-channel blockers, and nonsteroidal anti-inflammatory drugs could not have been used for at least 1 week before entry into the study. All patients were required to be able to achieve adequate symptomatic asthma control without using theophylline, oral -agonists, or antihistamines; none of these medications was permitted throughout the entire study period. Study Design and Intervention A randomized parallel design was used in this double-blind, placebo-controlled study. Patients were chosen randomly to receive either 600 mg of zileuton (four times a day), 800 mg of zileuton (twice a day), or placebo. A 1-week, single-blind, placebo lead-in qualification period (dummy lead-in period) was followed by random allocation to one of the three treatment groups for a 4-week, double-blind phase. During the single-blind, dummy lead-in and the double-blind study periods, all patients took capsules four times a day. Self-determined peak expiratory flow rates were recorded in the morning (before medication) and evening (2 hours after the third set of capsules) in a study diary. Albuterol inhaler use and asthma symptoms were recorded in the diary as well. Daytime asthma symptoms were self-rated on a scale of 1 to 5 (1 = no symptoms, 5 = severe symptoms; maximum weekly score of 35). After the 1-week dummy lead-in period, patients returned to their study center. Inhaled albuterol was withheld for at least 8 hours before the study visit. Spirometry was done on patients who had no clinically significant laboratory abnormalities, who had successfully completed their diary card, who had moderately symptomatic asthma (a total score of 12 but 28 in the previous 7 days), and who had used their albuterol inhaler at least 7 times during the dummy lead-in week. If the FEV1 was 40% to 75% of the predicted value, the patient was assigned randomly to a group according to a predetermined code. All patients took visually identical capsules four times per day that contained either 600 mg of zileuton four times daily, 800 mg of zileuton twice daily (active drug first and last dose daily), or placebo, which were supplied by Abbott Laboratories in a blind manner. The first dose of study medication was administered at the study center, and spirometry was done 30, 60, and 120 minutes later. In the 800-mg group, each days drug card contained both placebo and active drug, and as a result, on the first day, an undetermined number of patients received placebo instead of 800 mg of zileuton as their first dose of drug. Therefore, the 800-mg group was not included in the analysis of the acute response to the first dose of drug. During the 4-week double-blind period, patients returned to the study center at the same time of day on a weekly basis to have spirometry done and to review diary cards and medication use. During the second and third weeks of the double-blind randomization period, spirometry was also repeated 30 minutes after inhalation of two puffs of albuterol. Urine Collection and Analysis Urine was collected for 4 hours beginning at 8:00 a.m. before the dummy lead-in period and on day 28 of the study. Urinary LTE4 levels were determined by reverse-phase high-performance liquid chromatography and enzyme immunoassay using minor modifications of established procedures [29]. The recovery of the internal LTE4 standard was 74% 6%. The LTE4 content of the urine was expressed as picograms of immunoreactive LTE4 per milligram of creatinine. Adverse Events Routine complete blood counts, serum chemistries, urinalyses, and electrocardiograms were obtained throughout the study. Adverse symptoms were elicited daily through a diary question and were reviewed at the weekly visit to the study site. Statistical Analysis All values were expressed as means with associated 95% CIs; all outcome indicators were normally distributed. Paired t-tests were used to assess the statistical significance of any within-group changes from the baseline dummy lead-in phase. The statistical significance of differences among the placebo and active treatment groups during the 4 weeks of double-blind treatment was evaluated using a two-way analysis of variance model with effects for center, treatment, and center-treatment interaction. When statistical differences were noted among groups in the dummy lead-in, the groups were compared using an analysis of covariance adjusting for baseline differences. Available data were analyzed up to the point of withdrawal for patients who did not complete the study protocol. The Fisher test for the protected least significant difference was used to make pair-wise comparisons. Results Patients A total of 188 patients entered the single-blind dummy lead-in period; 143 fulfilled the enrollment criteria and were randomly assigned to receive study drug or placebo (46 patients received 2.4 g/d, 49 patients received 1.6 g/d, and 48 patients received placebo). Two patients withdrew during the first week of the double-blind study1 for personal reasons and the other because of worsening asthma (both received 1.6 g/d of zileuton). Two patients were not included in the final analysis, because they were enrolled in a center that did not have representation in all three treatment groups (1 received 1.6 g/d of zileuton and 1 received placebo). The characteristics of the 139 evaluated patients are given in Table 1. Of the 139 patients who were still in the trial after 1 week, 12 evaluated patients left the study before completing the trial protocol (all their data were included up to the point of termination): 4 patients because of worsening asthma (1 received 2.4 g/d, 2 received 1.6 g/d, and 1 received placebo); 2 patients because of upper respiratory infections (1 received 2.4 g/d and 1 received placebo); 1 patient because of sinusitis (placebo); 1 patient because of urticaria (1.6 g/d); 3 patients because of personal reasons (1 in each group); and 1 patient because of headaches that had begun before randomization (2.4 g/d). Table 1. Characteristics or Evaluated Patients* Acute Effects on Airway Obstruction A single 600-mg dose of zileuton produced rapid bronchodilation (Figure 1). Compared with the mean FEV1 measured just before study drug ingestion (0 minutes), the mean FEV1 improved 30 minutes after a single 600-mg dose of zileuton and remained increased for the entire 2-hour observation period (P < 0.005 for all observation points). The maximum increase (14.6%) in the mean FEV1 was 0.35 L (CI, 0.25 to 0.45 L) (P < 0.001), which occurred at 60 minutes. No improvement of the FEV1 occurred in the placebo group (0.09 L [CI, 0.01 to 0.19 L]; P = 0.075). The improvement in the mean FEV1 after zileuton was greater than that after placebo at 60 and 120 minutes (P < 0.001 and P = 0.01, respectively). Figure 1. Change in the forced expiratory volume during the 2 hours after administration of zileuton or placebo. P P P Effects of 4 Weeks of Zileuton Administration on Airway Obstruction All three groups of patients had an initial impr

Cetirizine in patients with seasonal rhinitis and concomitant asthma: prospective, randomized, placebo-controlled trial☆☆☆★★★

OBJECTIVE This study explored the safety and efficacy of cetirizine for treatment of allergic rhinitis and asthma. METHODS Daily treatment for 6 weeks with cetirizine 10 mg (93 patients) was compared with placebo treatment (93 patients) in a randomized, double-blind parallel study of patients with allergic rhinitis and asthma. This multicenter study was started just before onset of the fall pollen season. Rhinitis and asthma symptoms were assessed twice daily; spirometry was performed weekly. RESULTS Placebo-treated patients experienced a worsening of rhinitis symptoms from baseline throughout the study, whereas cetirizine-treated patients had a significant improvement in rhinitis symptoms at week 1, which was maintained after onset of the pollen season. Asthma symptoms in the cetirizine group improved from baseline at week 1; symptoms were significantly better than in the placebo group for 5 of 6 weeks of the study. Pulmonary function did not worsen in patients taking cetirizine or placebo; there were no differences between treatments as determined by spirometry. Albuterol use was less frequent in the cetirizine-treated patients for every week of the study, but differences did not reach significance. Pseudoephedrine use was similar in both groups. More cetirizine-treated patients (90%) completed the trial than did placebo-treated patients (74%). Both treatments were well tolerated. CONCLUSION Cetirizine 10 mg daily is safe and effective in relieving both upper and lower respiratory tract symptoms in patients with seasonal allergic rhinitis and concomitant asthma.

Effect of ciclesonide and fluticasone on hypothalamicpituitary-adrenal axis function in adults with mild-to-moderate persistent asthma

BACKGROUND Despite their proven efficacy in the treatment and prevention of asthma exacerbations, current inhaled corticosteroids carry safety concerns, especially adrenal suppression. Ciclesonide (hydrofluoroalkane propellant) is a novel inhaled corticosteroid with few, if any, clinical adverse events. OBJECTIVE To evaluate the potential effects of ciclesonide therapy on the dynamic cortisol response to sequential low- and high-dose cosyntropin stimulation in adults with mild-to-moderate persistent asthma. METHODS This was a double-blind, randomized, placebo-controlled, 12-week study in adults with mild-to-moderate asthma. One hundred sixty-four patients were randomized and treated; 148 patients completed the study. Fluticasone propionate (chlorofluorocarbon propellant) was used as an active comparator. The doses administered were 320 microg of ciclesonide once daily, 320 microg of ciclesonide twice daily, and 440 microg of fluticasone propionate twice daily, all doses ex-actuator. RESULTS For both ciclesonide groups, changes in mean low- and high-dose peak serum cortisol levels and in 24-hour urinary free cortisol levels corrected for creatinine were small vs baseline and comparable with placebo. For the fluticasone propionate group, significant reductions vs placebo in serum cortisol levels in response to high-dose cosyntropin stimulation and in 24-hour urinary free cortisol levels were observed. Oral candidiasis rates were 2.5% for 320-microg/d ciclesonide, 2.4% for 640-microg/d ciclesonide, and 22.0% for 880-microg/d fluticasone propionate. CONCLUSIONS These findings confirm the safety of ciclesonide therapy, demonstrating that at doses up to 640 microg/d, the drug does not affect sensitive markers of adrenal function.

Effectiveness and Safety of Fexofenadine, a New Nonsedating H1-Receptor Antagonist, in the Treatment of Fall Allergies

Fexofenadine HCl is a new, nonsedating H1-receptor antagonist approved for treatment of seasonal allergic rhinitis (SAR). In a double-blind, randomized, placebo-controlled, multicenter trial, 588 patients with fall SAR rated the severity of their symptoms using a scoring system at a screening visit and during a 3-day placebo lead-in period. Patients who did not respond to placebo and met symptom severity criteria were randomized to receive placebo or fexofenadine HCl at 40, 60, or 120 mg bid at 7:00 a.m. and 7:00 p.m. for 14 days. Patients continued to rate the severity of their symptoms immediately before receiving each dose (at trough). A total of 545 patients were included in an intent-to-treat analysis. The change from baseline in the primary efficacy variable (average daily 7:00 p.m. reflective symptom scores) was significantly greater in patients receiving all dosages of fexofenadine HCl than placebo (p < 0.01). All active dosages produced significant decreases (p < 0.05) in secondary end points: 7:00 a.m. reflective symptom scoring; 7:00 a.m. and 7:00 p.m. scoring 1-hour before dose; and bedtime scoring 1-3 hours after the 7:00 p.m. dose. All dosages of fexofenadine HCl were well tolerated, and no effect on QTc was observed. In conclusion, fexofenadine HCl is safe and effective in the treatment of fall SAR, with 60 mg bid being the optimal therapeutic dosage.

A clinical trial of ipratropium bromide nasal spray in patients with perennial nonallergic rhinitis

Intranasal ipratropium bromide has been shown to significantly reduce rhinorrhea. Use of a freon-propelled intranasal preparation has resulted in side effects associated with the drying properties of the propellant. The purpose of the present trial was to study the safety and efficacy of a new isotonic aqueous ipratropium bromide nasal spray pump, specifically in patients with perennial nonallergic rhinitis. Two hundred thirty-three patients participated in an 8-week double-blind parallel comparison of ipratropium bromide nasal spray with its vehicle, a saline solution. Treatment with the ipratropium spray resulted in a 30% reduction in rhinorrhea; this reduction was significantly greater than that seen with the saline vehicle. There was a modest reduction in postnasal drip, sneezing, and congestion with both treatments, which may be attributable to the salutary effects of the saline solution. Patients also perceived a significant reduction in the degree to which rhinorrhea interfered with their daily activities and moods. Treatment was well tolerated, with no drug-related systemic adverse events and no evidence of nasal rebound on discontinuation of treatment. Minor, infrequent episodes of nasal dryness and epistaxis were the only significant adverse events reported; these did not limit treatment.

Dose Ranging Study of Mometasone Furoate (Nasonex) in Seasonal Allergic Rhinitis

BACKGROUND Topical nasal corticosteroids are rapidly gaining acceptance as first-line therapy for seasonal allergic rhinitis, but there is a desire for effective corticosteroids with an improved safety profile over existing products. OBJECTIVE A multicenter, double-blind dose ranging study was conducted to compare the activity and tolerance of four doses of mometasone furoate nasal spray (tradename Nasonex) and placebo in adult patients with seasonal allergic rhinitis. METHODS Four hundred eighty patients with seasonal allergic rhinitis were enrolled and randomized to receive mometasone furoate nasal spray 50 micrograms (n = 96), 100 micrograms (n = 95), 200 micrograms (n = 98) or 800 micrograms (n = 95), or placebo vehicle (n = 95) once daily for 28 days. RESULTS All of the doses of mometasone furoate nasal spray showed activity in reducing the severity of rhinitis. The 200-microgram dose reduced total nasal symptom scores and total symptom scores throughout the study (P < .05 versus placebo vehicle). The 50-microgram dose and the 100-microgram dose showed less consistent activity at early timepoints (days 3 and 7), while the 800 microgram dose did not provide significant additional benefits over the 200-microgram dose. All dose levels were well tolerated CONCLUSION The results of this trial indicate that 200 micrograms once daily is the optimum dose of mometasone furoate nasal spray for the treatment of seasonal allergic rhinitis.

Efficacy and Safety of Nedocromil Sodium Ophthalmic Solution in the Treatment of Seasonal Allergic Conjunctivitis

To assess the efficacy and safety of twice-daily administration of nedocromil sodium 2% ophthalmic solution, we performed a multicenter study involving 140 patients with seasonal allergic conjunctivitis. Subjects had a history of seasonal allergic conjunctivitis and positive results of a skin test to ragweed. The trial coincided with the peak ragweed pollen season at five treatment centers. Patients treated with nedocromil sodium had improvements in symptoms with statistically significant reductions recorded for eye itching (P less than or equal to .04), conjunctival injection (P less than or equal to .001), and overall disease severity (P less than or equal to .001) as compared to the placebo-treated group. Adverse events were minor and transient. We concluded that nedocromil sodium 2% ophthalmic solution administered twice daily is effective in relieving major symptoms associated with seasonal allergic conjunctivitis.

Effects of budesonide by means of the Turbuhaler on the hypothalmic-pituitary-adrenal axis in asthmatic subjects: A dose-response study

BACKGROUND As a general phenomenon, corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects. OBJECTIVES This clinical trial was performed to assess the effects of budesonide on the HPA axis (at 800, 1600, or 3200 microg/day, given as a twice daily regimen, administered by means of the Turbuhaler) in adult patients with mild, non-steroid-dependent asthma. METHODS Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind, double-dummy, randomized, placebo-controlled, parallel-group, multicenter study. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone (ACTH), cosyntropin. RESULTS After 6 weeks of treatment, plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4% in the placebo group; by 13%, 11%, and 27% in the budesonide groups (800, 1600, and 3200 microg/day, respectively); and by 35% in the prednisone group. The decrease was significant only in the 3200 microg/day budesonide (p = 0.03) and prednisone (p = 0.005) groups. Over the same time period, decreases in basal plasma cortisol concentrations were 1% in the placebo group; 19%, 19%, and 34% in the three budesonide groups; and 37% in the prednisone group. Only in the prednisone group was the decrease significant (p = 0.03 vs placebo). CONCLUSIONS In this study budesonide inhaled by means of the Turbuhaler, at doses recommended for clinical use (800 or 1600 microg/day), did not produce any statistically significant suppression of the HPA axis compared with placebo.

Use of ipratropium bromide nasal spray in chronic treatment of nonallergic perennial rhinitis, alone and in combination with other perennial rhinitis medications

To study the long-term safety and effectiveness of ipratropium bromide nasal spray 0.03% in the treatment of nonallergic perennial rhinitis, we administered this medication for 1 year in an open-label trial involving 285 patients. Our intention was to maintain the highest protocol dose possible to gain a clearer picture of the long-term side effect profile of the compound. Ipratropium bromide was well tolerated with no serious side effects in this patient population. It provided a significant improvement in rhinorrhea throughout the year-long trial; only 17 of 285 patients (6%) were considered treatment failures. There was an improvement in patient quality of life, as well as a substantial reduction in the need for other medications (antihistamines, decongestants, and nasal steroids) used to treat perennial rhinitis symptoms.

A Preference Evaluation Study Comparing the Sensory Attributes of Mometasone Furoate and Fluticasone Propionate Nasal Sprays by Patients with Allergic Rhinitis

AbstractObjective: Data on intranasal corticosteroids suggest that individual product attributes may influence patient preference for therapy in allergic rhinitis. The study objective was to compare product sensory attributes and their impact upon patient preference for scent-free mometasone furoate nasal spray (MFNS) versus fluticasone propionate nasal spray (FPNS) in patients with symptomatic allergic rhinitis. Methods: In a double-blind, crossover study, 100 patients were randomized to MFNS 200μg followed by FPNS 200μg, or vice versa. Patients rated the study drugs by completing an individual product sensory attributes questionnaire at the end of each period of drug administration. An overall sensory preference questionnaire was completed following crossover. Results: A significantly greater number of patients preferred MFNS to FPNS (p < 0.05). MFNS was superior for a number of individual sensory attributes based on mean patient ratings: significantly fewer patients perceived scent/odor (immediately and 2 minutes after drug administration; p < 0.001), taste (immediately after drug administration; p = 0.002), and after-taste (2 minutes after drug administration; p = 0.007) with MFNS compared with FPNS. Similarly, product sensory attribute preference data demonstrated that twice the number of patients preferred MFNS to FPNS for scent/odor (p = 0.0005), immediate taste (p = 0.005), and after-taste (p = 0.005). Fifty-four percent of patients said they would choose a prescription for MFNS compared with 33% for FPNS (p = 0.03). In addition, 47% of patients would be more likely to comply (use daily as directed) with MFNS compared with 25% with FPNS (p = 0.03). Conclusion: Several individual sensory attributes of MFNS were rated significantly superior to FPNS. Overall, based on the tested sensory attributes, patients preferred MFNS to FPNS therapy for the treatment of allergic rhinitis.