Sheldon C. Siegel

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

Sinus disease in children with respiratory allergy.

Sinus disease has been assumed to exist in children with respiratory tract allergy, although a systematic evaluation of the relationship of these two processes has never been reported. We have been impressed that sinus involvement often adds significantly to the morbidity rate of allergic disease; when controlled or eliminated, the allergic respiratory process appears easier to control. This study was ‘undertaken to: (1) better define the prevalence of sinus disease in allergic children, and (2) establish clinical and laboratory diagnostic criteria.

Compliance of patients with asthma with an experimental aerosolized medication: Implications for controlled clinical trials

A Nebulizer Chronolog, a portable device that houses a standard nebulizer canister, was used in a unique method to measure compliance with aerosolized medication. Each actuation is tabulated to within 4 minutes of the actual time of usage and can subsequently be displayed in a day-hour-minute format. Of the 19 patients studied for 12 weeks with a cromolyn-like agent, appropriate usage four times a day ranged from 4.3% to 94.8%. Underusage exceeded overusage and ranged from 5.2% to 95% of the study days. Younger subjects and male subjects were less likely to use the aerosol appropriately. Patients failed to write the truth in their diaries with overreporting of appropriate usage more than 50% of the times. Lack of compliance with aerosolized medication represents an important medical issue for the physicians caring for patients with asthma. The Nebulizer Chronolog elicits new insight into the disparity between reported and observed compliance.

Effect of theophylline on gastroesophageal reflux in normal adults

In a randomized, double-blind manner, 15 normal adults were given a single oral loading dose of anhydrous theophylline (6.5 +/- 0.9 mg/kg) and nine normal adults were given placebo. All subjects were tested for serum theophylline levels, acid reflux (using intraesophageal pH probe), and lower esophageal sphincter pressure (LESP) at 1.5, 4, and 8 hr after treatment. Of subjects with negative baseline acid reflux tests, eight of 13 (61.5%) given theophylline developed positive acid reflux tests compared with none of eight subjects given placebo. One of nine (11%) placebo subjects reported heartburn compared with 11 of 15 (73%) subjects given theophylline. The maximum mean percent change in LESP from baseline was +5.62 +/- 28.8% in the placebo group and -25.01 +/- 23.7% in the theophylline group (p = 0.01) at 4 hr after treatment. While only two of nine (22%) adults given placebo had at least a 14% reduction in LESP following treatment, all of the 15 subjects sustained a minimum of 14% relaxation in LESP. This study confirms that oral theophylline at therapeutic serum levels inhibits LESP and induces gastroesophageal reflux (GER) measured by acid reflux tests in most normal adults.

A controlled study of cromolyn sodium sponsored by the Drug Committee of the American Academy of Allergy

Abstract Because of several controversial reports concerning the efficacy of cromolyn sodium in the treatment of asthma, the Drug Committee of the American Academy of Allergy instituted a collaborative study in November, 1969. The protocol was designed to select patients according to age, cooperativeness, severity of asthma, and type of asthma—extrinsic, intrinsic, or mixed. The basic design of the study involved a baseline period of one week in which inert filler (lactose) was administered in the Spinhaler apparatus and during which the patient could be familiarized with the complex record keeping. The basal period was followed by two 4 week crossover periods during which cromolyn sodium was alternated with placebo. Symptom scores, drug intake, physician evaluation, patient preference, and simple pulmonary function tests were subjected to statistical analysis. Results gleaned from 252 completed patients indicated a favorable response for the drug as compared to placebo in patient symptom scoring, ephedrine-like drug scores, physician evaluation, and patient preference. A drug carry-over effect extending over a period of 4 weeks created difficulty in assessing results of the placebo period in patients who received active drug during the first 4 week period. Although a favorable drug effect was usually observed when cromolyn sodium was the first drug in the trial sequence, efficacy was more clear-cut during active drug administration in patients who received placebo during the first 4 weeks of the study. The mechanism of this carry-over effect was not apparent. The amelioration index tended to be higher in the pediatric group and in those patients whose asthma was classified as mixed. No change in the objective indices of one-second forced expiratory volume or peak expiratory flow measured once every 2 weeks was obtained. No serious side effects were noted by the participating investigators. These results indicate that cromolyn sodium will be a useful adjunct to the pharmacological treatment of asthma.

Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma

BACKGROUND Many potential users of the H1 antihistamine cetirizine are asthmatic and may be using inhaled albuterol. This study was conducted to assess the possible bronchodilatory effect of cetirizine in patients with mild-to-moderate asthma and to determine whether cetirizine interacts with albuterol. METHODS In a randomized, double-blind, placebo-controlled, crossover study, the effects on pulmonary function of 5, 10, and 20 mg oral doses of cetirizine with and without inhaled albuterol (180 micrograms) were determined in 12 patients at 11 time points over 8 hours. The primary measure of efficacy was forced expiratory volume in 1 second (FEV1). RESULTS Cetirizine with or without albuterol significantly increased FEV1, peak expiratory flow rate, and forced expiratory flow rate between 25% and 75% of vital capacity relative to baseline and placebo but did not have a significant effect on forced vital capacity. The effect of 20 mg of cetirizine on FEV1 was generally greater than that of 10 or 5 mg, but the difference was statistically significant only at the 30-minute time point (p < 0.05). All three cetirizine doses produced significantly greater increases than placebo in FEV1 and forced expiratory flow rate between 25% and 75% of vital capacity for 8 hours and in peak expiratory flow rate for 7 hours (p < 0.02). Albuterol alone had a significant effect on the four pulmonary function variables from 1 to 5 hours after baseline (p < 0.05), which is consistent with albuterols recommended dosing frequency of every 4 to 6 hours. Albuterol alone increased FEV1 significantly more than 5 mg of cetirizine alone but not 10 mg or 20 mg of cetirizine alone at 60, 90, and 120 minutes after baseline, but all three doses of cetirizine increased FEV1 significantly more than albuterol 7 and 8 hours after baseline (p < 0.05), indicating that the bronchodilatory action of cetirizine lasts longer than that of albuterol. Cetirizine neither potentiated nor inhibited the bronchodilatory action of albuterol, but the two drugs appeared to have an additive bronchodilatory effect. None of the cetirizine treatments caused a worsening of pulmonary function, and all were well tolerated. CONCLUSIONS Cetirizine has a significant bronchodilatory effect in patients with mild-to-moderate asthma and can be used to treat concomitant conditions (e.g., allergic rhinitis) without concern that it will interfere with the bronchodilatory effect of albuterol or cause worsening of asthma by itself.

Efficacy of doxepin in the treatment of chronic idiopathic urticaria

Doxepin hydrochloride, a tricyclic antidepressant, was evaluated in a double-blind, placebo-controlled crossover trial for the treatment of chronic idiopathic urticaria in 16 adults. Efficacy was evaluated by symptom scores, concomitant antihistamine use, and suppression of histamine- and codeine-induced wheal response. Doxepin-treated subjects experienced fewer lesions (p less than 0.001), less waking hours with lesions (p less than 0.01), lesser degree of itch and/or discomfort (p less than 0.001), and less swelling or angioedema (p less than 0.001) as compared to placebo-treated subjects. Doxepin-treated subjects required less daily concomitant antihistamine use (mean 0.13 tablets versus 1.48 tablets, p less than 0.05). Doxepin also significantly suppressed histamine- and codeine-induced cutaneous wheal response as compared to placebo. Lethargy was commonly observed but diminished with continued use. Dry mouth and constipation were also commonly observed. We conclude that doxepin is an effective agent for the treatment of chronic idiopathic urticaria.

Topical intranasal corticosteroid therapy in rhinitis

This paper reviews the current clinical information on the newer corticosteroid aerosols used in the management of rhinitis: beclomethasone dipropionate, flunisolide, fluocortin butylester, budesonide, and triamcinolone acetonide. Discussed are their pharmacologic properties, including our most recent understanding of their possible mode of action, comparative efficacy to other agents, indications, side effects, and general educational principles regarding their use.

Gastroesophageal fundoplication for the management of chronic pulmonary disease in children

Gastroesophageal reflux is a common cause of chronic pulmonary disease in children. Forty-two children with recurrent pneumonia or severe asthma were evaluated and shown to have signicant reflux. Esophagography and esophageal pH testing proved the best diagnostic tests for determining reflux. Although the pulmonary symptoms were often due to repeated aspiration, they appeared in several cases to be related to bronchospasm caused by acid in the upper esophagus. All of the children underwent Nissen fundoplication and gastrostomy an average of 30 months after the onset of pulmonary symptoms. Of the children who had preoperative pneumonia, 87 percent had no recurrence after operation. In 13 of the 14 asthmatic children who underwent operation, symptoms improved and less bronchodilator medication was required. Morbidity and mortality were closely related to the duration and severity of pulmonary disease.

Chronic sinusitis in children with respiratory allergy: the role of antimicrobials☆

We evaluated the role of antimicrobials in the treatment of chronic maxillary sinusitis in children with respiratory allergy. Night and day cough, nasal obstruction, rhinorrhea, postnasal seen. Eighty-four children were treated in a double-blind manner with either amoxicillin, erythromycin, trimethoprim-sulfamethoxazole, or an antihistamine decongestant (carbinoxamine maleate-pseudoephedrine HCl). Radiographic and clinical responses were best with amoxicillin, but trimethoprim-sulfamethoxazole was an adequate alternative. This study demonstrates that allergic children with chronic sinusitis with associated chronic respiratory symptoms are likely to respond clinically and radiologically with antimicrobial treatment.