POSTER PRESENTATIONS

POSTER PRESENTATIONS POSTER PRESENTATIONS The following are summaries of posters presented at the XXI Congress of the European Academy of Allergology and Clinical Immunology, Naples, Italy, June1-5, 2002. EVALUATION OF ANTILEUKOTRIENES FOR PERENNIAL ALLERGIC RHINITIS Based on a poster presented by Agache I Faculty of Medicine, Clinical Immunology, Transylvania University, Brasov, Romania Perennial allergic rhinitis (PAR) is often comorbid with asthma, occurring in more than 75% of patients with allergic asthma and in more than 80% of patients with nonallergic asthma. 1,2 However, the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines note that in many instances, the symptoms predominate in one of the organs and may be hidden in the other. 3 First-line treatment for PAR, according to the ARIA guidelines, is either oral antihistamines or intranasal or topical corticosteroids. Antihistamines and corticosteroids act by different mechanisms of action to control the symptoms of PAR. For patients who are unable to achieve complete relief from PAR symptoms with antihistamines, corticosteroids may be more effective. This suggests that other mechanisms, in addition to histamine blockage, are affected by corticosteroids. One such mechanism may involve leukotrienes, which can cause nasal congestion and rhinorrhea; certain leukotrienes (LTC 4 and LTD 5 ) are 10 times more potent than histamine in causing nasal obstruction. 4 This study examined the effects on rhinitis symptoms of loratadine monotherapy, loratadine in combination with montelukast, and mometasone furoate monotherapy in patients with PAR. A secondary endpoint was the effect of these drugs in controlling the most common comorbid conditions with PAR: asthma, atopic dermatitis, and urticaria. A total of 69 patients with a 2-year history of PAR and positive skin-prick test for house dust mites, cats, and molds were randomized to receive loratadine 10 mg/day (Group A), mometasone 200 µg/day (Group B), or loratadine 10 mg/day plus montelukast 10 mg/day (Group C) for 6 months. Importantly, patients with unstable asthma or with a recent upper respiratory infection were excluded. Concomitant immunotherapy was permitted only if it had begun 1 year before the start of the study. Other PAR-controlling medications (eg, astemizole, corticosteroids, cromolyn, cetirizine, montelukast, ß-adrenergic agonists, other histamine-1 [H 1 ]-receptor antagonists, and short-acting antihistamines/decongestants) were prohibited prior to the start of the study. PAR symptoms were graded on a scale from 0 to 5 and a global symptom score was calculated at 0 and 6 months based on the main rhinitis symptoms: sneezing, nasal itch, secretion, and obstruction of nasal passages. Impact on comorbid allergic conditions was rated as no control, partial control, or total control. Symptom endpoint scores were analyzed as the average change from baseline to 6 months using an analysis of variance (ANOVA) model and Mann- Whitney U test. Secondary endpoint efficacy (ie, impact on comorbid conditions) was assessed using the Mantel-Haenszel test to determine percentage of patients in each classification. The results show significant improvement from baseline in sneezing, itching, nasal secretion, and global symptom score in Group A (loratadine alone) patients. Nasal obstruction also improved at 6 months but the difference was not significant. Group B patients (mometasone alone) showed significant improvement from baseline in nasal secretion and obstruction as well as global symptom scores. 882 Vol. 2, No. 24 November 2002

Improvements in sneezing and itching were also observed but were not significant. Patients in Group C (loratadine plus montelukast) showed significant improvements in every symptom endpoint compared with baseline (ie, sneezing, itching, nasal secretion, nasal obstruction, and global symptom score), significant improvements compared with Group A in nasal obstruction, and, compared with Group B, significant improvement in sneezing and itching. With regard to comorbid inflammatory conditions (ie, asthma, atopic dermatitis, and chronic urticaria), none of the patients in Group A (loratadine alone) experienced total control of any of the 3 comorbid conditions. Only 30% had partial control over atopic dermatitis, and 17% had partial control over chronic urticaria. However, Group C (combination therapy) patients experienced 91% control over asthma, with 4.5% each having partial or no control. A total of 80% of Group C patients had total control over atopic dermatitis, with 10% each having partial or no control. A total of 67% of those in Group C experienced complete control of chronic urticaria, compared with 17% each for partial and no control. The improved control of the comorbid conditions was significant between Groups C and A (ie, between combination therapy versus loratadine alone) only for those experiencing no control over asthma, atopic dermatitis, and chronic urticaria. Thus, significantly more patients failed to achieve control over asthma, atopic dermatitis, and chronic urticaria if they received loratadine alone versus combination therapy. Of note, no systemic or local side effects were reported during the study for any of the treatment regimens. Compliance in all 3 groups was very good, and the groups were well matched with regard to demographic characteristics. The benefits of combination loratadine plus montelukast for nasal symptoms have been shown in PAR. Rhinitis endpoints, however, were only modestly improved for those receiving either agent alone. 5 This study suggests even greater improvements in rhinitis symptoms with the combination of loratadine plus montelukast versus loratadine alone or mometasone alone in PAR. For controlling specific symptoms such as sneezing and itching, loratadine alone was better than mometasone alone. The effect on global scores was equivalent among all 3 treatment groups. Combination therapy was superior to loratadine alone in controlling nasal obstruction and was superior to mometasone alone in controlling sneezing and nasal itching. These results suggest that therapy can be tailored to each patient s specific symptoms. Combination therapy also better controlled the common comorbid conditions with PAR, thus may be used to treat these 2 conditions simultaneously. Larger trials are required to confirm these important and provocative findings. REFERENCES 1. Sibbald B, Rink E. Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history. Thorax. 1991;46(12):895-901. 2. Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol. 1999;104(2, pt 1):301-304. 3. Bousquet J. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2002;108(suppl 5):S147-S334. 4. Corren J. Allergic rhinitis: treating the adult. J Allergy Clin Immunol. 2000;105(6, pt 2):S610-615. 5. Meltzer EO, Malmstrom K, Lu S, et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol. 2000;105(5):917-922. MIZOLASTINE FOR THE TREATMENT OF ALLERGIC RHINOCONJUNCTIVITIS Based on a poster presented by Lleonart R,* Colás C, Peláez A, and Roger A *Hospital de Manresa, Allergy, Manresa, Spain; Hospital Clinico, Allergy, Zaragoza, Spain; Hospital Germans Tries i Pujol, Allergy, Badalona, Spain; Sanofi- Synthelabo, Medical, Barcelona, Spain Mizolastine has been approved for use in Europe for the treatment of allergic rhinitis. It is now under clinical investigation for the treatment of perennial allergic rhinoconjuctivitis. Mizolastine is one of the second-generation, histamine-1 (H 1 )-receptor antagonists that have been developed recently. It is nonsedating, well tolerated, and quickly absorbed; it has shown significant benefits against nasal and ocular symptoms as well as a reduction of nasal mucosal Advanced Studies in Medicine 883

eosinophilia, which accompanies allergic rhinitis. This observational study examined the effects of mizolastine on the signs and symptoms of perennial allergic rhinonconjunctivitis. More than 1000 patients in Spain received mizolastine 10 mg once daily. Signs were measured by the amount of nasal mucosa secretion and extent of nasal obstruction observed by rhinoscopy; symptoms such as nasal congestion, rhinorrhea, sneezing, and nasal pruritus were measured on a scale of 0 to 3. Patients were seen at 30 days and 90 days after baseline. The results show that all patients had improvement of both signs and symptoms at the 30-day follow-up visit. By 90 days, the signs and symptoms had improved even further, with the percentage of patients with normal nasal mucosa increasing from 7.4% at baseline to 67.4% at 90 days. Similarly, the percentage of patients with mucosal edema decreased from 74.7% to 32%, respectively. Complete nasal obstruction was also greatly reduced from 15.4% at baseline to 0.6% at Day 90 and the percentage of patients with nasal secretion decreased from 87% to 22%, respectively. Patients whose obstruction and secretions decreased by at least 50% were 61.1% and 69.8%, respectively. The nasal symptom scales show similar results. For example, at baseline, only1 patient felt asymptomatic while 22 had severe symptoms and 60 had moderate symptoms. By Day 90, 46 patients were asymptomatic and only 2 patients had several symptoms while 8 had moderate symptoms. Mizolastine was well tolerated with no serious adverse events reported and only 3% of the patients experiencing at least 1 adverse event. These data support the use of mizolastine as possible long-term treatment for perennial allergic rhinitis, although future randomized controlled studies are required. DRIVING ABILITY AFTER DIPHENHYDRAMINE VS LEVOCETIRIZINE SHOWS SIGNIFICANT DIFFERENCES Based on a poster presented by Volkerts ER, Verster JC, de Weert MM, Bijtjes SI, Aarab M, van Oosterwijck AM, Eijken EJ, and Verbaten MN Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands One of the biggest problems with the first-generation antihistamines is sedation, somnolence, or drowsiness, which are so strong that some patients are not able to drive or operate machinery while taking these medications. For those with seasonal or perennial allergic rhinitis, these adverse events are not acceptable. The second generation of antihistamine medications, the histamine-1 (H 1 )-receptor antagonists, offer significant clinical benefit without the hazards of these adverse events. Levocetirizine is a member of the second-generation antihistamines. It is the R-enantiomer of cetirizine, another well-known, second-generation, H 1 -receptor antagonist. This double-blind, placebo-controlled, randomized study examined the effects of levocetirizine (5 mg), diphenhydramine (50 mg), and placebo on the ability to drive in healthy volunteers. Diphenhydramine is notorious for its sedative side effects. The effects of these drugs on acute (1-day) and subchronic (4-day) administration were evaluated in 24 men and 24 women. A quantitative assessment on ability to drive was measured using the standard deviation of lateral position (SDLP). It is measured by a camera on the roof of a car; the lateral position of the car is measured relative to the painted stripe separating traffic lanes during normal traffic. When the SDLP increments exceed 35 cm, the subject is driving off the road, either onto the shoulder or into other lanes of traffic (www.pharm.uu.nl). The tests were performed at 1.5 hours after acute and subchronic administration of the study drugs. Participants were asked to drive at a steady speed of 95 km/h (57 mph) during the 100-km (75-minute) driving test. The results showed that only diphenhydramine (DPHD) caused significant changes in SDLP compared with the placebo group for both acute and subchronic dosages (17.7 cm placebo versus 20.5 cm DPHD, acute; 17 cm placebo versus 18.6 cm DPHD, subchronic). Changes in the levocetirizine group were 18 cm and 17.5 cm, respectively. Interestingly, reported adverse effects with diphenhydramine (ie, sleepiness, concentration difficulty, dry mouth, and dizziness) were significantly increased compared with placebo on Day 1. By Day 4, sleepiness with diphenhydramine was still greater than with placebo or levocetirizine, but the difference was not significant. Drowsiness, fatigue, and weakness were all more common in the diphen- 884 Vol. 2, No. 24 November 2002

hydramine group on Day 1, but were also decreased by Day 4. None of the differences in these symptoms were statistically significant compared with levocetirizine or placebo. The adverse effects with levocetirizine did not differ from those in the placebo group at Day 1 or Day 4. These results show that in a healthy population, levocetirizine does not affect the ability to drive and its adverse-effect profile is similar to that with placebo. Diphenhydramine can significantly impair driving ability with both acute and subchronic dosing, even when the drowsiness and sedative adverse events have decreased by Day 4. This information is important in deciding which antihistamine treatment to give patients with chronic rhinitis. FEXOFENADINE IS SAFE AND EFFECTIVE IN PEDIATRIC POPULATIONS WITH SEASONAL ALLERGIC RHINITIS Based on a poster presented by Wahn U,* with Hedin G, Ruuth E, La Rosa M, Kowalski M, and Simons E *Department of Pediatric Pneumology and Immunology, University Children s Hospital, Berlin, Germany; Karolinska Institute, Stockholm, Sweden; Aventis Pharma, CEDEX, France; Department of Pediatrics, Catania University, Catania, Italy; Department of Clinical Immunology and Allergy, Medical University, Lodz, Poland; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada. Fexofenadine is a selective, nonsedating histamine-1 (H 1 )-receptor antagonist that is approved for use in seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria. Its efficacy is well established in adults; in children, it has been shown to reduce the histamine-induced wheal and flare in 1 to 2 hours in children. 1 It has also been shown to be effective and nonsedating in children ages 6 to 11 years up to doses of 60 mg twice daily. 2 This study reports on the safety and efficacy of fexofenadine in children with SAR. It is one of the first placebo-controlled studies of fexofenadine in pediatric populations to assess all aspects of SAR symptoms. A total of 935 children from 148 centers in 15 countries were randomized to receive either placebo (n = 471) or fexofenadine (n = 464) 30 mg twice daily every 12 hours (7:00 AM and 7:00 PM) with no instructions regarding food intake with dosing. This was a double-blind, randomized, placebo-controlled, parallel-group study that included children 6 to 11 years of age with a 1-year history of spring or fall SAR. The doubleblind treatment phase lasted 14 days. Efficacy was assessed by determining the total symptom score and the score of nasal congestion in particular. The total symptom score was determined by rating the following symptoms at baseline and at 7:00 PM daily (± 1 hour): sneezing; rhinorrhea; itchy nose, mouth, throat, and/or eyes; itchy, watery, red eyes; and nasal congestion. Patients rated each symptom on a scale of 0 (absent) to 4 (very severe). The results show a significant decrease in total symptom score in the fexofenadine group, with an overall decrease of 0.73 points (P =.001) compared with placebo (1.94 vs 1.21, respectively). Importantly, all individual components of the symptom scoring system were significantly improved with fexofenadine treatment up to P <.0001 (mean change in symptom score compared with placebo). Nasal congestion also significantly improved (P <.01). Fexofenadine was safe and well tolerated. The severity of types of adverse events were similar between the 2 groups, with the most common being headache (2.8% placebo; 5% fexofenadine). A total of 25 children reported at least 1 adverse event that was possibly related to treatment (n = 14 fexofenadine; n = 11 placebo). These results support earlier studies showing the safety and efficacy in pediatric populations. This large, double-blind, placebo-controlled study showed that fexofenadine can improve all symptoms associated with SAR, including nasal congestion, with minimal or no side effects. REFERENCES 1. Graft DF, Bernstein DI, Goldsobel A, Meltzer EO, Portnoy J, Long J. Safety of fexofenadine in children treated for seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2001;87(1):22-26. 2. Simons FE, Bergman JN, Watson WT, Simons KJ. The clinical pharmacology of fexofenadine in children. J Allergy Clin Immunol. 1996;98(6, pt 1):1062-1064. Advanced Studies in Medicine 885

THE NEUROPSYCHOLOGICAL IMPLICATIONS OF ANTIHISTAMINE TREATMENT Based on a poster presented by Wilken JA* with Kane RL *Veterans Affairs Medical Center, Neuropsychology, Washington, DC; Veterans Affairs Medical Center, Neuropsychology, Baltimore, Maryland One of the biggest advantages of second-generation antihistamines (histamine-1 [H 1 ]-receptor antagonists) is their lack of sedative effects, especially compared with first-generation products. While the central nervous system (CNS) effects of first- and second- generation antihistamines have been studied, little research has been done that assesses the level of cognitive dysfunction associated with first-generation antihistamines relative to other disorders of the CNS. This study compared the neuropsychological effects of a known sedating antihistamine (diphenhydramine) with a nonsedating, second-generation antihistamine (desloratadine) in patients subjected to induced allergic rhinitis. Using the published literature, the measured effects on cognitive functioning and vigilance from this study were compared with other disorders known to affect the CNS. More than 240 patients participated in the study, with roughly 80 in each treatment group: diphenhydramine 50 mg, desloratadine 5 mg, or placebo. Baseline testing occurred before priming. Rhinitis was induced in the study participants by priming with ragweed pollen, and the neuropsychologic battery of tests were performed 90 minutes after dosing. The test battery included measures of vigilance (eg, alertness) and cognitive functioning (eg, working memory, divided attention, psychomotor speed, and reasoning). The battery took about 45 minutes to complete. The results showed, as expected, that both drugs significantly decreased the symptoms associated with seasonal allergic rhinitis (SAR) compared with placebo. Symptom severity was assessed via subject self-report. Subjects rated 8 individual nasal and nonnasal SAR signs and symptoms. All subjects were required to have a total symptom severity score of greater than 10, a total nasal symptom score of greater than 6, and a total nonnasal symptom score of greater than 4 at the completion of the priming phase, at the symptomatic baseline assessment, and on the treatment day prior to the dispensing of the study medication. Subjects again recorded symptoms after completion of the performance battery. Diphenhydramine-treated patients performed significantly worse than those taking desloratadine or placebo on all measures of vigilance and cognitive functioning. Those receiving desloratadine did not experience decrements in either vigilance or cognition. On measures of cognitive functioning, desloratadine patients were similar to those in the placebo group. On measures of vigilance, a non-significant trend toward better functioning compared with placebo was observed in desloratadine subjects, which may be explained by improvement in rhinitis status. Of particular note was the comparison of vigilance and cognitive effects of diphenhydramine relative to desloratadine compared with other CNS disorders. To determine this, the differences in effect sizes between the desloratadine and diphenhydramine subjects were established for all vigilance and cognitive measures. A literature review of mild head injury, migraine, mild hypoxia, and toxins was refined for measures of vigilance, working memory, divided attention, psychomotor speed, and reasoning. For each CNS condition, an effect size was determined based on the published values for each cognitive domain. The effect sizes for the difference in performance between desloratadine and diphenhydramine subjects was within the confidence interval of effect sizes for many of the CNS conditions. For vigilance, the effect size for the desloratadine-diphenhydramine difference was even greater than that of patients with hypoxia in other studies. For working memory, the desloratadinediphenhydramine effect size was greater than that of patients with migraines or exposed to toxins. Thus, the adverse effects of diphenhydramine on vigilance and cognitive functioning are similar to adverse effects experienced by those with conditions caused by mild, diffuse CNS impairment. The investigators suggest that the efficacy of firstgeneration antihistamines, such as diphenhydramine, must therefore be considered in the context of their sedative and cognitive effects. Thus, the risk-to-benefit ratio, especially compared with second-generation antihistamines, should be assessed. Additionally, the use of certain nonsedating secondgeneration antihistamines, such as desloratadine, appears to improve symptoms without adversely affecting cognitive functioning. 886 Vol. 2, No. 24 November 2002