Melvyn Danzig

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log10 of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04–0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.

Effective dose range of mometasone furoate nasal spray in the treatment of acute rhinosinusitis

BACKGROUND Mometasone furoate nasal spray (MFNS) 400 microg, twice daily, as adjunctive treatment with oral antibiotic significantly improved symptoms of recurrent rhinosinusitis. OBJECTIVE To evaluate the effectiveness and safety of MFNS 200 microg, twice daily, and 400 microg, twice daily, compared with placebo as adjunctive treatment with oral antibiotic for acute rhinosinusitis. METHODS In this multicenter, double-blind, placebo-controlled study, 967 outpatients with computed tomographic scan-confirmed moderate to severe rhinosinusitis received amoxicillin/clavulanate potassium (Augmentin, GlaxoSmithKline, Research Triangle Park, NC) 875 mg, twice daily, for 21 days with adjunctive twice daily MFNS 200 microg, MFNS 400 microg, or placebo nasal spray. Patients recorded scores of six rhinosinusitis symptoms and any adverse events twice daily. Pre- and postcosyntropin-stimulation plasma cortisol levels were measured in a subset of patients at selected study sites. RESULTS Treatment with MFNS 200 microg or 400 microg, twice daily, produced significantly greater improvements in total symptoms score (primary efficacy variable) day 1 to day 15 average (50% and 51%, respectively) than placebo (44%, P < or = 0.017). Both doses of MFNS produced significant total symptoms score improvement over placebo by day 4, and maintained efficacy over the entire 21-day study. Relief of individual symptoms showed a similar pattern. Both doses of MFNS were well tolerated, and adverse events were similar to that of placebo. Cosyntropin stimulation showed no evidence of hypothalamic-pituitary-adrenal axis suppression. CONCLUSIONS As adjunctive therapy to oral antibiotic treatment, MFNS at doses of 200 microg or 400 microg, twice daily, was well tolerated and significantly more effective in reducing the symptoms of rhinosinusitis than antibiotic therapy alone.

Comparative Effects of Desloratadine versus Montelukast on Asthma Symptoms and Use of β2-Agonists in Patients with Seasonal Allergic Rhinitis and Asthma

Background: Asthma and seasonal allergic rhinitis (SAR) are recognized as manifestations of a single airway disease. Desloratadine has demonstrated efficacy in treating SAR symptoms, including nasal obstruction. Methods: Safety and efficacy of desloratadine and montelukast each were assessed in a double-blind, placebo-controlled trial of patients with SAR and symptoms of asthma, who were assigned randomly to once-daily treatment with desloratadine 5 mg, montelukast 10 mg, or placebo for 4 weeks. Change from baseline of AM/PM reflective total asthma symptom severity scores (TASS), FEV1, individual asthma symptom scores, and β2-agonist usage were assessed. Results: Desloratadine and montelukast each were associated with statistically significant reductions from baseline in the mean TASS averaged over the 4-week period (p ≤0.022 vs. placebo). Individual asthma symptom scores also improved significantly for both therapies (p ≤ 0.05). Patients treated with desloratadine or montelukast demonstrated improvement from baseline in FEV1 versus placebo; significant improvement was seen in a subset of patients with baseline FEV1 <80% of predicted normal (both p < 0.05). Both active therapies significantly reduced β2-agonist use (both p < 0.01). Improvements for both therapies were comparable for all efficacy parameters; they were tolerated well with adverse event profiles similar to placebo. Conclusions: Asthma symptoms and β2-agonist were improved significantly in patients with concomitant SAR and asthma treated with desloratadine 5 mg as well as montelukast 10 mg once daily. Both therapies significantly improved FEV1 in a subset of patients with FEV1 <80% of predicted normal at entry. Improvements in asthma symptoms were comparable for both active treatment groups.

Rhinosinusitis: Developing guidance for clinical trials

The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication, “Rhinosinusitis: Establishing definitions for clinical research and patient care” and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.

Loratadine treatment of rhinitis due to pollen allergy reduces epithelial ICAM-1 expression.

Background Loratadine and cetirizine are new generation antihistamines, which are clinically effective in the treatment of allergic rhinitis.

Protective Effect of Loratadine on Late Phase Reaction Induced by Conjunctival Provocation Test

The protective effect of Loratadine, a new generation, non-sedating antihistamine, on clinical and cellular events during the early phase reaction (EPR) and late phase reaction (LPR) of the allergen-specific conjunctival provocation test (CPT) was assessed out of the pollen season in 20 seasonally allergic rhino-conjunctivitis patients. After a screening CPT, selected patients were randomized to Loratadine (10 mg OD) or matching placebo for 7 days. CPT was repeated following treatment. Clinical and cellular responses were evaluated by a symptom score and cell counting in conjunctival scrapings before, and 30 min and 6 h after challenge with allergen (one eye) or placebo (control eye). Conjunctival symptom severity following CPT was reduced at 30 min (EPR) and 6 h (LPR) after CPT in the Loratadine group compared to placebo group (p < 0.01), as was the total number of inflammatory cells (p < 0.001). In conclusion, Loratadine protects against the clinical and cellular EPR and LPR events consequent to CPT, showing antiallergic properties.

Prophylactic management of children at risk for recurrent upper respiratory infections: the Preventia I Study

Background Given the morbidity and mortality of asthma and the recent dramatic increase in its prevalence, pharmacologic prophylaxis of this disease in children at risk would represent a major medical advance.

A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber.

BACKGROUND Studies on the efficacy of phenylephrine in the treatment of nasal congestion have yielded inconsistent results, notwithstanding its approval for this indication. OBJECTIVE To evaluate and compare the decongestant effect of a single dose of phenylephrine to placebo and pseudoephedrine in patients with seasonal allergic rhinitis. METHODS This randomized, placebo-controlled, 3-way crossover study evaluated patient-scored nasal congestion, peak nasal inspiratory flow, and rhinomanometry at more than 6 hours in 39 grass-sensitive patients exposed to grass pollen in the Vienna Challenge Chamber. Patients were dosed with immediate-release formulations of phenylephrine, 12 mg, pseudoephedrine, 60 mg, as a control, or placebo. RESULTS Phenylephrine was not significantly different from placebo in the primary end point, mean change in nasal congestion score at more than 6 hours (P = .56), whereas pseudoephedrine was significantly more effective than both placebo (P < .01) and phenylephrine (P = .01). Phase 1 results showed a difference between phenylephrine and placebo that was 64% of the difference between pseudoephedrine and placebo, substantially greater than the 17% difference observed for all phases. Carryover bias due to patient recall of the pseudoephedrine effect may have influenced these results. Rhinomanometry and peak nasal inspiratory flow results were consistent with these data. Neither phenylephrine nor pseudoephedrine had an effect on the nonnasal symptoms. No adverse events were reported in this study. CONCLUSIONS During a 6-hour observation period, a single dose of pseudoephedrine but not phenylephrine resulted in significant improvement in measures of nasal congestion. Neither phenylephrine nor pseudoephedrine had an effect on nonnasal symptoms.

Onset of symptomatic effect of mometasone furoate nasal spray in the treatment of nasal polyposis

BACKGROUND The efficacy of the intranasal corticosteroid mometasone furoate nasal spray (MFNS) for treatment of nasal polyposis was demonstrated in 2 large clinical trials. OBJECTIVE To evaluate the onset of MFNS symptomatic effect, data from the 2 trials were pooled and analyzed to determine the first day subjects experienced significant symptom relief. METHODS Subjects with nasal polyposis randomized to MFNS 200 microg twice daily or placebo scored symptoms on a 3-point scale (0 = none; 3 = severe) and measured peak nasal inspiratory flow immediately before the morning dose. Onset of symptomatic effect was defined as the first day a statistically significant (P < .05) lasting response was observed for MFNS compared with placebo. RESULTS A total of 447 subjects with bilateral nasal polyps and clinically significant nasal congestion/obstruction were analyzed. Compared with placebo, MFNS 200 microg twice daily demonstrated statistically significant (P < .05) relief of anterior rhinorrhea by day 2 (-10.9% vs +5.7%), nasal congestion by day 3 (-15.1% vs -7.6%), postnasal drip by day 5 (+1.1% vs +4.6%), and sense of smell by day 13 (-9.6% vs -5.6%). Significant improvement in peak nasal inspiratory flow was seen by day 2 (increase of 6.22 L/min vs 1.48 L/min for placebo; P = .03). CONCLUSION Mometasone furoate nasal spray 200 microg twice daily rapidly improves the symptoms of nasal polyposis, leading to lasting relief of most major symptoms within 2 (24 hours after the first dose) to 5 days of initiating therapy.

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 lE 0.05) relief of rhinorrhea and nasal stuffiness as compared with placebo. Insomnia was reported significantly more often (P < 0.01) in Claritin-D 12 Hour (15%) patients compared with Claritin-D 24 Hour (4%) and placebo (2%) patients. Dry mouth was reported significantly more often (P < 0.05) in Claritin-D 24 Hour (13%) and Claritin-D 12 Hour (13%) groups compared with placebo (4%). Claritin-D 24 Hour has efficacy comparable to Claritin-D 12 Hour in relieving allergic rhinitis symptoms while producing significantly less insomnia.