Immunotherapy With the SQ Tree SLIT-tablet in Adults and Adolescents With Allergic Rhinoconjunctivitis

Purpose: The SQ tree sublingual immunotherapy (SLIT)-tablet containing allergen extracts with the major allergen Bet v 1 from birch pollen is currently being developed for the treatment of tree pollen induced allergic rhinitis/conjunctivitis with or without asthma. The aim of this Phase II trial was to investigate the dose-related efficacy and safety of the SQ tree SLIT-tablet. Methods: This study was a randomized, parallel group, double-blind, placebo-controlled, multi-national trial conducted in Europe. A total of 637 participants were randomized equally to receive placebo or treatment with the SQ tree SLIT-tablet in doses of 0.5, 1, 2, 4, 7, or 12 development units (DU). Treatment was initiated 16 weeks before onset of the 2013 birch pollen season (BPS) and was continued throughout the BPS with a total duration of at least 6 months. During the BPS and tree pollen season (TPS), subjects assessed rhinoconjunctivitis symptoms and medication use on a daily basis in an electronic diary; weekly assessments of rhinoconjunctivitis quality of life were also made. Findings: Analysis of the average daily symptom score during the BPS and the TPS showed that the difference between active treatment and placebo was statistically significant for the 7 DU group (BPS, P = 0.02; TPS, P = 0.03), with no clear dose response relationship. All doses of the SQ tree SLIT-tablet induced changes from baseline in birch-specific IgE and IgG(4) that were statistically significant compared with placebo at all time points assessed (P = 95%) being mild or moderate in severity. The most frequently reported treatment related adverse events were generally related to the sublingual administration of the tablet (ie, they occurred in the oral cavity). (C) 2018 Elsevier HS Journals, Inc. All rights reserved.Peer reviewe

Aspirin-Exacerbated Respiratory Disease: Evaluation and Management

The clinical syndrome of aspirin-exacerbated respiratory disease (AERD) is a condition where inhibition of cyclooxygenase-1 (COX-1) induces attacks of upper and lower airway reactions, including rhinorrhea and varying degrees of bronchospasm and laryngospasm. Although the reaction is not IgE-mediated, patients can also present with anaphylactic hypersensitivity reactions, including hypotension, after exposure to COX-1 inhibiting drugs. All patients with AERD have underlying nasal polyps and intractable sinus disease which may be difficult to treat with standard medical and surgical interventions. This review article focuses on the management of AERD patients with a particular emphasis on aspirin desensitization and continuous treatment with aspirin

Leukotriene modifiers for asthma treatment

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB 4 , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT 1 and CysLT 2 , have been identified. The activation of the CysLT 1 receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB 4 might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT 1 receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT 1 receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT 1 receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT 1 receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment.Cite this as: P. Montuschi and M. L. Peters-Golden, Clinical & Experimental Allergy , 2010 (40) 1732–1741.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79154/1/j.1365-2222.2010.03630.x.pd

Tolerance to coxibs in patients with intolerance to non-steroidal anti-inflammatory drugs (NSAIDs): a systematic structured review of the literature

Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966–2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966–2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous

Patienters upplevelser av för dem viktiga komponenter vid behandling av utmattningssyndrom

Utmattningssyndrom, som bland annat innefattar påtaglig brist på psykisk energi, är en relativt ny svensk diagnos. Det saknas fortfarande i hög grad forskning kring effektiv behandling, trots att likartade tillstånd rapporteras internationellt. Syftet med denna studie var att undersöka patienters upplevelser av en behandling av utmattningssyndrom och därigenom öka förståelsen för vad de tycker är viktiga komponenter i denna. Fem informanter, som har genomgått gruppbehandling på Stressmottagningen, har intervjuats och materialet har analyserats induktivt tematiskt. Viktiga komponenter enligt informanterna är att hantera skam och lära sig acceptans, att sätta upp mål och strukturera problemen, att få kontakt med kroppen, att hantera ickefunktionella tankar, att testa nya beteenden, att lära sig gränssätta samt att öka sin tillit. Många poängterar vikten av adekvat vård i rimlig tid och efterlyser kompletterande individuell behandling. Acceptans och hantering av skam tycks vara centrala komponenter, som kan kräva ytterligare fokus i framtida forskning och behandling

Clinical studies of asthma phenotypes focusing on the role of the leukotrienes

Inflammation in the airways in connection to asthma is a complex phenomenon and the mechanisms underlying the associated clinical symptoms involve the interaction of many different kinds of cells and mediators, giving rise to different phenotypes. The aim of the present thesis was to investigate the molecular and cellular mechanisms that results in two of these phenotypes, i.e., aspirinintolerant asthma and allergic asthma. The main focus was on leukotrienes and other eicosanoids, metabolites of arachidonic acid, and the major experimental approach employed was bronchial challenge. Thirty-three subjects known to be suffering from aspirin-intolerant asthma were challenged with celecoxib a selective inhibitor of COX-2. Both escalating doses from 5-100 mg (administered in a blinded, placebo-controlled study) and an open label challenge with 200 + 200 mg celecoxib were tolerated well by these individuals. This finding indicates that the intolerance reaction leading to bronchoconstriction in patients with aspirin-intolerant asthma is due to inhibition of COX-1 and, furthermore, provides a scientific basis for administration of selective inhibitors of COX-2 to alleviate prostaglandin-mediated pain and inflammation in these patients. With the ultimate objective of finding a marker that can be used to identify patients with leukotrieneassociated asthma, the capacity to produce leukotrienes and responsiveness to inhaled leukotrienes was determined in 20 subjects with intermittent-to-mild asthma and 10 healthy control individuals. Neither group exhibited a correlation between the formation of LTB4 by their whole blood in response to ex vivo stimulation or urinary levels of LTE4 and airway responsiveness to LTD4. In further attempts to predict which asthmatic patients will respond well to antileukotriene treatment, investigations on the capacity for leukotriene synthesis and responsiveness to these agents and expression of their specific receptor in the lungs are presently being performed. When 8 individuals with allergic asthma were challenged repeatedly with low doses of allergen, the level of nitric oxide in the air they exhaled and their responsiveness to histamine rose significantly. At the same time, these subjects did not report any symptoms of asthma, required rescue by bronchodilator medication or display any change in the calibre of their airways. Accordingly monitoring of exhaled nitric oxide on a daily basis might allow for early detection of exacerbation in subjects with allergic asthma. Thirteen patients with allergic asthma were subjected to bronchial challenges with methacholine and LTD4 prior to and after administration of 500 µg fluticasone twice daily for two weeks, and their levels of exhaled nitric oxide and urinary LTE4 was determined. Inhalation of glucocorticoid attenuated the responsiveness to methacholine and reduced the level of exhaled nitric oxide, but neither the responsiveness to LTD4 nor urinary excretion of LTE4 was affected. Thus, neither the release nor the actions of leukotrienes appear to be sensitive to inhaled glucocorticoids, strengthening the rationale for using a combination of glucocorticosteroids and antileukotrienes to treat allergic asthma. In summary, we have shown the following here: 1) There is now a rationale basis for using selective inhibitors of COX-2 to alleviate prostaglandin mediated-pain and inflammation in individuals with aspirin-intolerant asthma. 2) The bronchial responsiveness of subjects with asthma cannot be predicted on the basis of the ability of their whole blood to produce LTB4 in response to stimulation ex vivo or their urinary levels of LTE4. 3) Regular monitoring of exhaled nitric oxide might allow early detection of exacerbation in subjects with allergic asthma. 4) There is a mechanistic rationale for combination treatment of allergic asthma with glucocorticosteroids and antileukotrienes

Relation between bronchial responsiveness to inhaled leukotriene D(4) and markers of leukotriene biosynthesis

Background: While clinical trials with antileukotrienes have shown overall beneficial effects in asthma, the factors that determine leukotriene dependent asthma are still unclear. A study was undertaken to determine whether or not leukotriene responsiveness in the airways correlates with endogenous leukotriene biosynthesis. Methods: Bronchial responsiveness to leukotriene (LT) D(4) was assessed as PD(20)FEV(1) in 20 subjects with mild asthma and 10 healthy controls, and compared with bronchial responsiveness to methacholine and two global measures of leukotriene production—urinary LTE(4) and ex vivo production of LTB(4) in whole blood. Results: In patients with asthma the bronchoconstrictor activity of LTD(4) was about 1300 times greater than methacholine (geometric mean PD(20) 0.69 nmol v 887 nmol). Those who were most responsive to LTD(4) were relatively less responsive to methacholine (p<0.01). There was, however, no correlation between bronchial responsiveness to LTD(4) and urinary LTE(4) or blood ex vivo LTB(4) levels in asthmatic subjects or healthy controls. Subjects with asthma treated with inhaled corticosteroids produced higher levels of LTB(4) (p<0.05). Conclusions: General measures of leukotriene production cannot predict bronchial responsiveness to LTD(4). The unique bronchoconstrictive potency of LTD(4) on human airways may relate to the locally regulated expression of the cysteinyl LT(1) receptor