Michel Melac

Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis

BACKGROUND Recombinant DNA technology has the potential to produce allergen-specific immunotherapy vaccines with defined composition. OBJECTIVE To evaluate the effectiveness of a new recombinant birch pollen allergen vaccine in patients with birch pollen allergy. METHODS A multicenter, randomized, double-blind, placebo-controlled trial was undertaken to compare the following 3 vaccines in 134 adults with birch pollen allergy: recombinant birch pollen allergen vaccine (rBet v 1a), licensed birch pollen extract, natural purified birch pollen allergen (nBet v 1), and placebo. Patients received 12 weekly injections followed by monthly injections of the maintenance dose containing 15 microg Bet v 1 for 2 years. RESULTS Significant reductions (about 50%) in rhinoconjunctivitis symptoms (rBet v 1, P = .0002; nBet v 1, P = .0006; birch extract, P = .0024), rescue medication (rBet v 1, P = .0011; nBet v 1, P = .0025; birch extract, P = .0063), and skin sensitivities (P < .0001) were observed in the 3 actively treated groups compared with placebo during 2 consecutive pollen seasons. Clinical improvement was accompanied by marked increases in Bet v 1-specific IgG levels, which were higher in the rBet v 1-treated group than in the birch and nBet v 1-treated groups. New IgE specificities were induced in 3 of 29 patients treated with birch pollen extract, but in none of the 32 rBet v 1-treated or 29 nBet v 1-treated patients. No severe systemic adverse events were observed in the rBet v 1-treated group. CONCLUSION The rBet v 1-based vaccine was safe and effective in treating birch pollen allergy, and induced a highly specific immune response.

Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber

BACKGROUND The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. OBJECTIVE We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. METHODS Patients with grass pollen-induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. RESULTS In the intention-to-treat population (n = 89) a significant treatment effect was achieved after the first month (P = .0042) and second month (P = .0203) and was maintained through to the fourth month (P = .0007). In the active group the ARTSS (means +/- SDs) decreased at each challenge: week 1, 7.40 +/- 2.682; month 1, 5.89 +/- 2.431; month 2, 5.09 +/- 2.088; and month 4, 4.85 +/- 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergen-specific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. CONCLUSIONS In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.

Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis.

BACKGROUND Seasonal allergic rhinoconjunctivitis affects millions of persons. The efficacy of allergen sublingual immunotherapy (SLIT) was demonstrated in previous short-term studies. OBJECTIVES We sought to evaluate the sustained efficacy of 2 dosing regimens of a pre- and coseasonal treatment with 300 IR (index of reactivity) 5-grass-pollen SLIT tablets (Oralair) compared with placebo assessed by using the average adjusted symptom score (AAdSS) at season 3 in adults with grass pollen-induced rhinoconjunctivitis. METHODS Six hundred thirty-three patients were treated for either 2 or 4 months before and then during the grass pollen season with active or placebo treatment for 3 consecutive seasons. The primary outcome was the AAdSS, a symptom score adjusted for rescue medication use, after 3 consecutive treatment seasons. Secondary outcomes were symptoms and rescue medication score, quality-of-life, and safety assessments. RESULTS The mean AAdSS was reduced by 36.0% and 34.5% at season 3 in the 2- and 4-month pre- and coseasonal active treatment groups, respectively, compared with that in the placebo group (P < .0001 for both). Reductions were observed in total symptom scores and ISSs and the medication score, with a marked improvement in quality of life for both active groups compared with the placebo group at season 3. Most treatment-emergent adverse events were local reactions expected with SLIT, decreasing in number and intensity in each treatment season. CONCLUSIONS Sustained efficacy of 2- and 4-month pre- and coseasonal treatment with the 300 IR tablet over 3 pollen seasons was demonstrated, with reduction in symptoms and rescue medication use. The treatment was well tolerated. Adverse events decreased in number and intensity over the 3 seasons.

Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy.

Background:  The optimal dose of five‐grass pollen sublingual tablet immunotherapy (SLIT) was established recently by the primary criteria Rhinoconjunctivitis Total Symptom Score (RTSS) from the first treatment season. Secondary and exploratory criteria, such as RTSS at peak pollen season, exploratory combined symptom and rescue medication use score, quality of life and immunological markers are calculated and described in this analysis.

Safety and tolerability of grass pollen tablets in sublingual immunotherapy--a phase-1 study.

Background:  A single‐centre, randomized, double‐blind, placebo‐controlled study.

Drug Therapy and Memory Training Programs: A Double-Blind Randomized Trial of General Practice Patients With Age-Associated Memory Impairment

A double-blind randomized trial was performed involving 162 patients with age-associated memory impairment (AAMI) selected and followed by their general practitioners. Two intervention methods--a drug and a cognitive therapy--were assessed in combination. Three randomized parallel groups of 54 patients each, aged 55 years and over, were followed and treated for 3 months. After a placebo wash-out period of 10 days, one group received 2.4 g of piracetam, another group, 4.8g, and the third, a placebo. A total of 135 patients, 45 in each group, completed the study. Combined therapy was most effective in patients whose baseline performance on memory tests was lowest. The best results were observed with 4.8 g of piracetam, especially when training sessions began after 6 weeks of drug treatment. This result was confirmed by the global impression of the principal investigator.

Twenty-four hours of activity of cetirizine and fexofenadine in the skin.

BACKGROUND Cetirizine and fexofenadine, the active metabolite of terfenadine, are powerful and well-tolerated H1 receptor antagonists effective in the treatment of skin and nose atopic diseases. OBJECTIVE We have compared the pharmacodynamic activity of the two antihistamines at therapeutic dosages, cetirizine at 10 mg and fexofenadine at 120 mg and 180 mg, on histamine-induced skin reactivity during a 24-hour period after single intake. METHODS Twenty-six healthy volunteers participated in a randomized, double-blind, crossover, placebo-controlled study. The areas of wheal and flare induced by histamine (100 mg/mL) administered by prick test were measured at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose. Statistical analysis of the areas under the time-response curves was performed by a Friedmans ANOVA followed by a Wilcoxon test and Bonferronis correction. RESULTS The three active treatments clearly inhibited the wheal and flare areas throughout the 24-hour period compared with placebo. Maximal inhibition occurred at 4 hours postdose. Between 4 and 24 hours postdose, the time course of inhibition by cetirizine differed significantly (P < 0.001) from that by fexofenadine at either dose, which did not differ from each other. At 24 hours, fexofenadine inhibited <40% of the skin reaction, whereas cetirizine reduced 60% of the wheal. The duration of effect, considered as the time for wheal to be inhibited by at least 70%, also significantly favored cetirizine (19 hours) compared with fexofenadine (9.3 and 8.5 hours for 180 and 120 mg, respectively; P < 0.001). Consistency of activity was evaluated by the frequency of total inhibition of the wheal (> or =95%). Consistency was observed in 26 of 26 participants for cetirizine, 21 of 26 for fexofenadine, 180 mg, and 10 of 26 for fexofenadine, 120 mg (P < 0.001), suggesting better consistency for cetirizine. There was no serious adverse event. CONCLUSIONS Our study clearly shows better duration of action and consistency of the antihistaminic activity of cetirizine compared with fexofenadine (120 and 180 mg) in the histamine-induced skin reaction during a 24-hour period.

Consistency of the Efficacy of Cetirizine and Ebastine on Skin Reactivity

BACKGROUND At therapeutic dosage, cetirizine and ebastine induce significant inhibition of skin reactivity to histamine. The consistency of their efficacy, that is, efficacy with the least interindividual variability among subjects, has not been carefully assessed, however. OBJECTIVE To compare the consistency and efficacy of these antihistamines on skin reactivity. METHODS Twenty-four healthy volunteers participated in a randomized double-blind crossover study. The areas of wheals and flares induced by increasing (0, 5, 10, 50, 100, 200, and 300 mg/mL) histamine concentrations, administered by prick tests, were measured before and four hours after intake of 10 mg of each antihistamine, allowing concentration-response curves to be established. The threshold histamine concentrations inducing wheal areas of 3 mm2 (positivity) were calculated by interpolation. The coefficient of variation (SD/mean %) was used to evaluate the consistency of the response. RESULTS Pretreatment concentration-response curves were similar, and threshold concentrations identical (0.29 mg/mL and 0.34 mg/mL for cetirizine and ebastine, respectively). For both, curves were lower after treatment than before. After cetirizine, the threshold concentration was significantly higher (217 mg/mL) than after ebastine (0.82 mg/mL) (P < .001), and total inhibition of the wheal reaction was observed in 21 of 24 patients at the lowest histamine concentration and in 17 of 24 at the highest. Ebastine never totally inhibited reaction, even to 5 mg/mL of histamine. Over the entire concentration-response curve, the coefficient of variation for the wheal reaction was 6.3% for cetirizine and 72.6% for ebastine, and, for flares, 11.0% and 83.7%, respectively. Hence, variability was much lower after cetirizine. CONCLUSION Our study shows clearly that the efficacy of a single therapeutic dosage of cetirizine is consistently good for suppression of cutaneous reactivity to histamine in healthy volunteers. The need for ebastine to metabolize into the active carebastine might explain its lesser consistency.

Comparison of Efficacy and Safety of Cetirizine and Ebastine in Patients with Perennial Allergic Rhinitis

BACKGROUND Cetirizine and ebastine are two second-generation histamine H1 antagonists undergoing evaluation for treatment of perennial rhinitis. OBJECTIVE The clinical efficacy and safety of once daily cetirizine 10 mg were compared with ebastine 10 mg in patients with perennial allergic rhinitis in a 4-week, double-blind, parallel-group, randomized, multicenter study. METHOD Two hundred fourteen patients (120 females, 94 males, aged 17 to 70 years, mean 31.2 years) were selected on the basis of perennial allergic rhinitis history, positive skin test for perennial allergens and a minimum rhinitis symptom score of 6/12. Patients recorded nasal symptom severity (nasal stuffiness, nasal discharge, sneezing, and itching) once daily on diary cards using a rating scale of 0 (none) to 3 (severe). Clinicians made an overall evaluation after 4 weeks of treatment. An intent-to-treat-analysis was performed comparing cetirizine (106 patients) and ebastine groups (108 patients). RESULTS The individual and total baseline symptom scores were comparable in both treatment groups. During the first week, the percentage mean decrease in the total nasal symptom score from baseline (sum of nasal stuffiness, discharge, sneezing, and itching) was significantly higher for cetirizine 46.2% than for ebastine 32.8% (P = .037). After 4 weeks of treatment, total symptom score improvement was 53.7% for cetirizine and 44.7% for ebastine (P = .12), and the clinicians overall evaluation showed that the percentage of symptom-free patients was significantly higher for cetirizine 17.8% than for ebastine 6.9% (P = .02). Cetirizine also significantly improved nasal stuffiness. An associated antiinflammatory effect is suggested. Commonly reported drug-related side effects were similar in both groups. CONCLUSION This study shows that both antihistamines, cetirizine 10 mg and ebastine 10 mg once a day, improved symptom scores of patients with perennial allergic rhinitis. Cetirizine, however, provided faster improvement and total relief in a greater number of patients after 4 weeks.

Onset of action in the nasal antihistaminic effect of cetirizine and loratadine in patients with allergic rhinitis

Several studies have compared the cutaneous efficacy of cetirizine and loratadine and their onset of action. We assessed the nasal effect of these two antihistamines in a randomized, double‐blind, crossover, placebo‐controlled trial in order to compare objectively their efficacy and onset of action in the noses of patients with allergic rhinitis. Nasal challenge was performed by nebulization of increasing doubling doses of histamine (0, 0.04‐1.28 mg/nostril) in 12 patients (eight men, four women, aged 22‐39 years). Nasal airway resistance (NAR) was measured by posterior rhinomanometry either 1.5 h or 4 h after intake of cetirizine (10 mg), loratadine (10 mg), or placebo. Baseline NAR was identical between all study days (2.60‐2.88 cmH2O·1−1·s). One and a half hours after intake, the increase in NAR induced by histamine was significantly reduced by both cetirizine and loratadine in contrast to placebo. However, with cetirizine the nasal obstruction was significantly lower than with loratadine (P<0.05). Four hours after intake, a similar inhibition of the nasal obstruction caused by histamine was observed with both cetirizine and loratadine (P<0.05). In conclusion, this study found cetirizine and loratadine to have similar nasal efficacy at therapeutic dosage 4 h after intake, whereas cetirizine was more effective than loratadine 1.5 h after intake. In agreement with the results observed in the skin, our study suggests a more rapid onset of action of cetirizine in the nose in allergic rhinitis.