1,721,105 research outputs found
Treatment guidelines for asthma - Where will leukotriene receptor antagonists fit in?
No full textThis article reviews the evidence for the involvement of leukotrienes in asthma and the effect of antagonists in clinical models of the disease. It also discusses how these new drugs might be used in asthma management.</p
Medical pharmacology and Therapeutics: Dedication
No full textTo our families. Medical Pharmacology & Therapeutics, now in its fifth edition, offers medical students all they need to know to become safe and effective prescribers. It forms a complete, integrated resource for basic pharmaceutical science, pathophysiology, clinical pharmacology, and therapeutics
Anti-leukotrienes in asthma and allergic rhinitis.
No full textLeukotrienes are lipid mediators synthesized from arachidonic acid liberated from the membranes of activated inflammatory cells [1]. The subfamily of cysteinyl-leukotrienes (cys-LTs) represented by LTC4, LTD4 and LTE4 are the first inflammatory mediators to have a proven role in the pathophysiology of asthma [2] and which mimic many of the features of allergic rhinitis [3]. Antileukotriene drugs that block the synthesis of leukotrienes or antagonize cys-LT receptors have been licensed for asthma therapy in most countries in the last dozen years [4], with some of these drugs also being registered for use in allergic rhinitis [2]. This chapter will outline the sources and actions of cys-LTs in allergic airway inflammation and the clinical evidence underlying the use of antileukotriene drugs in asthma and allergic rhinitis
Effects of celecoxib augmentation of antidepressant or anxiolytic treatment on affective symptoms and inflammatory markers in patients with anxiety disorders: exploratory study
No full textProlonged stress has been associated with elevated levels of circulating proinflammatory cytokines. Cyclo-oxygenase-2 inhibitors such as celecoxib exert anti-inflammatory effects and may enhance the response to antidepressant drug treatment in patients with depressive disorders, but their effect on anxiety symptoms in patients with anxiety disorders is uncertain. Patients with a primary diagnosis of an anxiety disorder, with stabilised symptoms, underwent either 6 weeks of celecoxib augmentation of continued treatment (n = 18) or continued 'treatment as usual' (n = 9). Assessments included the Warwick-Edinburgh mental well-being Scale (WEMWEBS), Hospital Anxiety and Depression Scale (HADS), Oxford questionnaire of emotional side effects of antidepressants (OQUESA) and Clinical Global Impression of Illness Severity (CGI-S). Venous blood samples were collected for assays of inflammatory cytokines. Patients who underwent celecoxib augmentation showed significant reductions in anxiety (HADS-A-3.17) and depressive (HADS-D-2.11) symptoms and in overall illness severity (CGI-S-1.11), and improvements in mental well-being (WEMWBS 7.5) and positive changes in emotional responsiveness (OQUESA-RP-3.56; OQUESA-AC-4.22): These were not seen with 'treatment as usual'. There were no significant changes in blood levels of inflammatory cytokines in either group. Celecoxib augmentation appeared associated with beneficial effects on anxiety and depressive symptoms and mental well-being. The findings from this pilot study merit further exploration within a double-blind, randomised placebo-controlled study.</p
The effect of inhaled leukotriene B<sub>4</sub> in normal and in asthmatic subjects
No full textLeukotriene (LT) B4 is a potent leukocyte chemotaxin that increases bronchial responsiveness in animal models. In a double-blind, placebo- controlled crossover study we examined the effects of LTB4 on lung function, bronchial responsiveness, and blood leukocyte counts in six normal subjects and in six subjects with mild asthma who inhaled mean ± SEM doses of 17.6 ± 3.4 and 18.2 ± 1.9 μg LTB4, respectively, or placebo. There were no significant changes in specific airway conductance or bronchial responsiveness in either normal subjects or asthmatics for as long as 24 h after inhalation. In the normal subjects, LTB4 rapidly reduced blood neutrophil counts to 19.8 ± 6.3% of baseline at S min (p = 0.0003 compared with placebo), followed by a neutrophilia of 307 ± 40% of baseline at 30 min (p = 0.007). Similar changes occurred in asthmatics, with a neutropenia at 5 min (69.6 ± 5.8%; p = 0.003) and a neutrophilia at 30 min (183 ± 17.2%; p = 0.037). The neutrophilia was not sustained in either subject group, with values being no different from that of placebo by 6 h. The asthmatics had significantly less neutropenia (p = 0.005) and less neutrophilia (p = 0.018) than did the normal subjects. Placebo inhalation had no effect on any parameter in either group. The smaller neutrophil responses in asthmatics may reflect desensitization of blood neutrophils in vivo because of chronic exposure to endogenous LTB4.</p
IL-5 increases expression of 5-lipoxygenase-activating protein and translocates 5-lipoxygenase to the nucleus in human blood eosinophils
No full textCysteinyl-leukotrienes are potent bronchoconstrictor mediators synthesized by the 5-lipoxygenase (5-LO) pathway. Eosinophilopoietic cytokines such as IL-5 enhance Cysteinyl-leukotriene synthesis in eosinophils in vitro, mimicking changes in eosinophils from asthmatic patients, but the mechanism is unknown. We hypothesized that IL-5 induces the expression of 5- LO and/or its activating protein FLAP in eosinophils, and that this might be modulated by anti-inflammatory corticosteroids. Compared with control cultures, IL-5 increased the proportion of normal blood eosinophils immunostaining for FLAP (65 ± 4 vs 34 ± 4%; p < 0.0001), enhanced immunoblot levels of FLAP by 51 ± 14% (p = 0.03), and quadrupled ionophore- stimulated leukotriene C4 synthesis from 5.7 to 20.8 ng/106 cells (p < 0.02). IL-5 effects persisted for 24 h and were abolished by cycloheximide and actinomycin D. The proportion of FLAP+ eosinophils was also increased by dexamethasone (p < 0.0001). Neither IL-5 nor dexamethasone altered 5-LO expression, but IL-5 significantly increased 5-LO immunofluorescence localizing to eosinophil nuclei. Compared with normal subjects, allergic asthmatic patients had a greater proportion of circulating FLAP+ eosinophils (46 ± 6 vs 27 ± 3%; p < 0.03) and a smaller IL-5-induced increase in FLAP immunoreactivity (p < 0.05). Thus, IL-5 increases FLAP expression and translocates 5-LO to the nucleus in normal blood eosinophils in vitro. This is associated with an enhanced capacity for cysteinyl-leukotriene synthesis and mimics in vivo increases in FLAP expression in eosinophils from allergic asthmatics.</p
Leukotriene antagonists and synthesis inhibitors: New directions in asthma therapy
No full textThis article briefly reviews the advances in our understanding of asthma with a particular focus on the role of inflammation, before providing a concise overview of current knowledge of leukotrienes in the pathophysiology of the disease. The development of leukotriene receptor antagonists and synthesis inhibitors is briefly described; and acute exercise, allergen, and aspirin challenge studies with these agents are reviewed. Clinical studies with leukotriene antagonists and inhibitors have confirmed the central role of leukotrienes in asthma pathophysiology. In conclusion, we suggest that the new generation of leukotriene receptor antagonists may be suitable as first-line therapy in patients with mild to moderate asthma. Further studies are required to determine whether the leukotriene synthesis inhibitors will be equally effective or provide any additional antiinflammatory benefit.</p
Effect of inhaled prostaglandin D<sub>2</sub> in normal and atopic subjects, and of pretreatment with leukotriene D<sub>4</sub>
No full textBackground - Prostaglandin (PG) D2 is a potent bronchoconstrictor mediator and is found, together with leukotriene (LT) D4, in bronchoalveolar lavage fluid during the early response to allergen challenge in asthmatic subjects. The potency of PGD2 has not been established in normal and atopic non-asthmatic subjects, nor has the contribution of cholinergic mechanisms to PGD2 induced bronchoconstriction in normal subjects. Mediators released simultaneously may interact, so the effect of pre-inhalation of LTD4 on PGD2 responsiveness was investigated. Methods - Six normal and six atopic non-asthmatic subjects performed histamine and PGD2 challenges on separate occasions. Eight normal subjects performed PGD2 challenges immediately before and 45 minutes after inhalation of 200 μg oxitropium bromide or placebo. Bronchial responsiveness to PGD2 was established in six normal subjects immediately after pretreatment with saline or non- bronchoconstricting doses of methacholine or LTD4 (challenge 1), and again at six hours (challenge 2). All studies were performed in a double blind, randomised, crossover fashion. Results - PGD2 was 25-fold and 18-fold more potent as a bronchoconstrictor than histamine in atopic non-asthmatic and normal subjects, respectively. Responsiveness (PC35sGaw) to histamine and PGD2 correlated significantly (r=0.917, n=12, p<0.001). Oxitropium bromide in a dose of 200 μg inhibited PGD2 induced bronchoconstriction by 37.5%, although in two of these subjects no inhibition was seen. Pre-inhalation of LTD4 and methacholine shifted the dose-response curve of PGD2 to the left by 4.6-fold and 2.4-fold, respectively. Conclusions - PGD2 is a potent bronchoconstrictor in normal subjects, which is partly mediated by cholinergic mechanisms in some subjects. No significant interaction was found between LTD4 and PGD2 in six normal subjects.</p
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