Introduction Le remibrutinib, un inhibiteur de la tyrosine kinase de Bruton (BTK) hautement sélectif administré par voie orale, a déjà démontré une efficacité supérieure à celle du placebo à la semaine 12 et un profil de tolérance favorable au cours des études de phase 3 REMIX-1 et -2 chez des patients souffrant d’urticaire chronique spontanée (UCS). Nous rapportons ici les données à long terme de ces études. Matériel et méthodes REMIX-1 et REMIX-2 sont deux études multicentriques, randomisées, en double aveugle, contrôlées par placebo, évaluant l’efficacité et la sécurité d’emploi du remibrutinib chez des patients atteints d’UCS insuffisamment contrôlés par les antihistaminiques H1. Les patients ont été randomisés 2:1 pour recevoir 25mg de remibrutinib par voie orale deux fois par jour ou un placebo pendant une période de 24 semaines en double aveugle, suivie de 28 semaines de traitement en ouvert (jusqu’à 52 semaines de traitement au total). Les critères d’évaluation principaux étaient le changement par rapport à l’inclusion 1) du score hebdomadaire d’activité de l’urticaire (UAS7) et 2) des scores hebdomadaires de sévérité du prurit (ISS7) et de gravité de l’urticaire (HSS7) à la semaine 12. Les critères secondaires principaux étaient la proportion de patients ayant obtenu un contrôle total de leur symptôme (UAS7=0) à la semaine 12 et une maladie bien contrôlée (UAS7≤6) aux semaines 2 et 12, ainsi que la survenue d’événements indésirables. Tous les critères d’évaluation ont été réévalués aux semaines 24 et 52. Résultats Dans REMIX-1 et -2, 313 et 300 patients ont été randomisés pour recevoir 25mg de remibrutinib deux fois par jour, respectivement, et 157 et 155 ont été randomisés pour recevoir un placebo, respectivement. À la semaine 12, le remibrutinib a montré des améliorations supérieures à celles du placebo des scores UAS7, ISS7 et HSS7, qui se sont maintenues jusqu’à la semaine 24. À la semaine 24, le remibrutinib a montré une amélioration par rapport au placebo (moyenne des moindres carrés) des scores UAS7 (REMIX-1 : –20,9 vs –16,0 ; REMIX-2 : –20,5 vs –14,0), ISS7 et HSS7. Une augmentation significative du nombre de patients atteignant un score UAS7≤6 a été observée dès la semaine 2 avec le remibrutinib par rapport au placebo. Significativement plus de patients ont atteint un score UAS7≤6 et UAS7=0 à la semaine 12 avec le remibrutinib vs le placebo, avec un maintien jusqu’à la semaine 24. Le remibrutinib a été bien toléré, avec un profil d’évènements indésirables généralement comparable au placebo. Discussion Les études sont terminées ; les données de la semaine 52 sont disponibles et pourront être présentées. Conclusion Le remibrutinib a montré une efficacité dès la semaine 2, qui s’est maintenue jusqu’à la semaine 24, avec un profil de tolérance favorable dans ces études de phase 3, soutenant son potentiel en tant que nouveau traitement oral pour les patients atteints d’UCS insuffisamment contrôlés par les antihistaminiques H1.

Objectives: Specific recommendations for administering the influenza vaccine to patients with egg allergy are based on limited scientific data. The objectives of this investigation were to determine the safety of a 2-dose administration of an influenza vaccine to patients with egg allergy and to evaluate the usefulness of skin testing with the influenza vaccine before administration.Study design: In this multicenter clinical trial, clinical histories of egg allergy were confirmed by skin testing with egg and, if possible, by oral challenges with egg. Subjects with egg allergy received the vaccine in 2 doses, 30 minutes apart; the first dose was one tenth and the second dose nine tenths of the recommended dose as determined by age. Subjects without egg allergy were recruited as control subjects and received 1 age-determined dose of the vaccine. Skin pride tests with the influenza vaccine were performed on all subjects.Results: From 1994 to 1997, 83 subjects with egg allergy and 124 control subjects were evaluated. The content of ovalbumin/ovomucoid was 0.1, 1.2, and 0.02 mu g/mL, respectively in the 1994-95, 1995-96, and 1996-97 influenza vaccines. Results of vaccine skin prick tests were positive in 4 subjects with egg allergy and in 1 control subject. All patients with egg allergy tolerated the vaccination protocol without any significant allergic reactions.Conclusions: These results demonstrate that patients with egg allergy, even those with significant allergic reactions after egg ingestion, can safely receive an influenza vaccine in a 2-dose protocol when the vaccine preparation contains no more than 1.2 mu g/mL egg protein.

A previous New Zealand case-control study of asthma deaths in the 5-45 year age group during 1981-3 found that prescription of fenoterol (by metered dose inhaler) was associated with an increased risk of death in patients with severe asthma. One major criticism of this study was that drug data for the cases and controls came from different sources. A new case-control design has been used to evaluate the same hypothesis, with a different set of asthma deaths, the same source for drug information being used for both cases and controls. This depended on identifying deaths from asthma during 1977-81 from national mortality records, and ascertaining which patients from those who died had been admitted to a major hospital for asthma during the 12 months before death. The study was confined to this subgroup, which accounted for about 20% of all asthma deaths in the areas served by a major hospital. For each of the eligible patients who died four age matched controls were selected from patients admitted to hospital for asthma during the year that the death occurred who had also had an admission for asthma in the previous 12 months. For the 58 cases and 227 control subjects information on prescribed drugs was collected from the hospital records relating to the previous admission. The odds ratio of asthma death in patients prescribed inhaled fenoterol was 1.99 (95% confidence interval 1.12-3.55, p = 0.02). As in the previous study, subgroups defined by markers of chronic asthma severity were also considered. The inhaled fenoterol odds ratio was 2.98 (95% CI 1.15-7.70, p = 0.02) in patients prescribed three or more categories of asthma drugs, 3.91 (95% CI 1.79-8.54, p less than 0.01) in patients with a previous admission for asthma in the past 12 months, and 5.83 (95% CI 1.62-21.0, p = 0.01) in patients prescribed oral corticosteroids at the time of admission. In patients with the most severe asthma (defined by a previous admission for asthma during the past 12 months and prescribed oral corticosteroids at time of admission) the inhaled fenoterol odds ratio was 9.82 (95% CI 2.23-43.4, p less than 0.01). These findings add further support to the hypothesis that inhaled fenoterol increases the risk of death in patients with severe asthma.

Inhalation of nebulised water can provoke bronchoconstriction in asthmatic patients. In the first part of this study, a community survey identified that about 20% of patients with home nebulisers currently use water as a diluent. In the second part of this study, the airways effect of the use of water as a diluent for nebulised beta agonist was investigated. Nineteen asthmatic subjects were administered nebulised 2.5 mg salbutamol, diluted with either 2 mL water or physiological saline, and forced expiratory volume in one second (FEV1) was measured at baseline and at regular intervals for 45 minutes after nebulisation. Although there was a trend towards a reduced bronchodilator response with water as diluent, the differences between the two diluents were not significantly different. Paradoxical bronchoconstriction was not observed when salbutamol was diluted with water. We conclude that the common practice of diluting bronchodilator nebuliser solution with water does not result in a significant reduction in the overall bronchodilator response.

Chlorbutol is an antibacterial and antifungal agent incorporated in terbutaline (Bricanyl) nebulizer solution. Ten stable atopic asthmatic subjects undertook bronchial challenge testing, according to a double-blind protocol. Patients inhaled doubling concentrations of either methacholine (0.13-4.0 mg.ml-1) or chlorbutol (0.16-5.0 mg.ml-1) for 2 min until the forced expiratory volume in one second (FEV1) had fallen by 20% from baseline. If this had not occurred following the administration of the final concentration, then this highest concentration was repeated for 4 min. The nine subjects completing the study had a geometric mean provocation concentration producing a 20% fall from baseline FEV1 (PC20) methacholine of 0.16 mg.ml-1 (range less than 0.125-0.475 mg.ml-1). After inhalation of 2.5 mg.ml-1 chlorbutol one subject experienced a fall in FEV1 greater than 20%. In the remaining eight subjects, inhalation of chlorbutol did not affect airway calibre. We conclude that chlorbutol, in the concentration present in Bricanyl nebulizer solution, has no clinically significant effect on airway calibre.

In this double blind study, the cardiovascular and hypokalaemic effects of equal doses of inhaled pirbuterol and salbutamol were compared in eight healthy volunteers. Increasing doses of 200, 400, 600 and 800 micrograms (total dose 2000 micrograms) were given from a metered dose inhaler at 15 min intervals, followed by measurement of heart rate, blood pressure, total electromechanical systole (QS2I) (as a measure of inotropic response) and plasma potassium (K+) concentration 15 min after each inhalation. After inhalation of the highest concentration, salbutamol resulted in a greater increase in heart rate (10.5 bpm vs 4.4 bpm, p less than 0.0007), and reduction in QS2I (-25.4 ms vs -9.6 ms, p less than 0.0001) than pirbuterol. There were no significant differences in changes in systolic blood pressure (1.9 mmHg vs 6 mmHg, p = 0.27), diastolic blood pressure (-5.8 mmHg vs -3.9 mmHg, p = 0.64) or plasma K+ (-0.21 mmol/L vs -0.15 mmol/L, p = 0.57). We conclude that the new beta-2 adrenergic agonist pirbuterol is at least as beta-2 selective as salbutamol when administered by repeated inhalation in healthy volunteers.

We have investigated whether oral theophylline potentiated the cardiovascular effects of fenoterol administered by metered-dose inhaler. Eight healthy subjects were investigated on four occasions. On successive days (1 and 2), the subjects were given doses of 400 micrograms, 600 micrograms, and 800 micrograms of fenoterol at 15-minute intervals (total dose, 1.8 mg) or matched placebo. Systolic time intervals, blood pressure, and the ECG were recorded at baseline and five minutes after each inhalation. Thereafter, the subjects were treated with slow-release theophylline for eight days. On days 9 and 10, the procedures on days 1 and 2 were repeated. The order of treatment was applied according to a crossover Latin-square design. The effects after theophylline alone were no different from placebo. Theophylline potentiated those hemodynamic effects of fenoterol due to enhanced cardiac sympathetic tone (mean +/- SE) as measured by a decrease in Q-S2I (-41.6 +/- 7.6 ms vs -27.3 +/- 5.9 ms; p = 0.0004), an increase in systolic BP (23.5 +/- 2.8 mm Hg vs 9.0 +/- 5.3 mm Hg; p = 0.00001), and an increase in heart rate (15.8 +/- 1.6 bpm vs 9.1 +/- 3.7 bpm; p = 0.0013). The responses mediated by beta 2-adrenergic receptor stimulation, namely, a decrease in PEP and diastolic BP, were not potentiated. Although fenoterol prolonged the Q-Tc interval and decreased T-wave amplitude, these effects were not potentiated by theophylline. Oral theophylline potentiates the positively inotropic and chronotropic effects of fenoterol.