Nedocromil Sodium

Publisher Website
Google Scholar
Abstract
Nedocromil sodium, the disodium salt of a pyranoquinoline dicarboxylic acid, has anti-inflammatory properties in vitro, in animal models of asthma, and in humans, as evidenced by inhibition of inflammatory cell activation and mediator release, early and late allergen-induced bronchoconstriction and airway hyperresponsiveness. Recent therapeutic trials confirm the safety and efficacy of inhaled nedocromil sodium as adjunctive therapy in adult patients whose asthma is not adequately controlled by β-agonists alone. Nedocromil sodium has also been shown to improve symptoms when added to existing treatment with methylxanthines and corticosteroids. Some studies show nedocromil sodium to be successful replacement therapy for methylxanthines, in addition to enabling a modest reduction in inhaled corticosteroids in some patients. Thus, nedocromil sodium may be suitable in patients with asthma as an adjunct to existing therapy, as an alternative to regularly administered oral and inhaled β-agonists and oral methylxanthines, and potentially, to low dose inhaled corticosteroids as maintenance therapy in patients with mild to moderate asthma being considered for corticosteroid therapy. In vitro, nedocromil sodium inhibits chemotaxis of eosinophils and neutrophils induced by a variety of stimuli. In addition, nedocromil sodium inhibits the release of leukotriene C4, and histamine from mast cells obtained from healthy and asthmatic volunteers by bronchoalveolar lavage, and of granulocyte-macrophage colony-stimulating factor from human bronchial epithelium, in vitro and in vivo. At usual therapeutic dosages, nedocromil sodium administered for several weeks, decreased airway responsiveness to inhaled methacholine. Exercise-induced asthma was inhibited more effectively by nedocromil sodium than by placebo, although this effect was not clearly dose related. Nedocromil sodium inhibited the early and late asthmatic reaction to inhaled house dust mite allergen. Bronchoconstriction induced in patients with asthma by a wide variety of stimuli was also inhibited by nedocromil sodium. In these studies, nedocromil sodium was generally more effective than sodium cromoglycate (cromolyn sodium). It is apparent from results of experimental studies that nedocromil sodium exerts its antiinflammatory effect by regulation of a variety of actions on polymorphonuclear leucocytes, macrophages and epithelial cells. The specific mechanisms by which nedocromil sodium exerts it regulatory action on these inflammatory cells remain unclear. Following inhalation of nedocromil sodium 4mg mean peak plasma concentrations of approximately 3 μg/L in healthy volunteers and patients with asthma, respectively, are attained within a mean period of 20 minutes. These concentrations are transiently increased by at least 50% by vigorous exercise, a series of forced expiratory measurements, and both manoeuvres combined. Bioavailability is 6 to 9% after inhalation of nedocromil sodium 4mg. The drug is not metabolised after intravenous administration, with 64% recovered in urine and 36% recovered in faeces 96 hours after intravenous administration. Protection against bronchoconstriction induced by adenosine monophosphate was provided by inhaled nedocromil sodium 4mg, but not when administered orally (80mg) or intravenously (6 μg/kg). Studies published since the previous review of nedocromil sodium in the Journal confirm the efficacy of inhaled nedocromil sodium compared with placebo when added to existing treatment, with inhaled and orally administered β2-agonists and/or methylxanthines, and in some studies, inhaled or oral corticosteroids. In patients whose asthma was not adequately controlled by their existing regimen, the addition of nedocromil sodium improved symptomatic control and lung function while reducing the requirement for inhaled bronchodilators. In comparisons with sodium cromoglycate, nedocromil sodium has shown similar or greater efficacy. On the basis of comparisons with beclomethasone dipropionate, although results varied between patients, nedocromil sodium 16mg daily appeared to be approximately equivalent to inhaled beclomethasone dipropionate 400μg daily in improving symptoms of asthma and pulmonary function when added to existing therapy. When substituted for regular maintenance therapy in patients whose asthma was adequately controlled at the start of the trial, substitution of nedocromil sodium 4mg twice or 4 times daily for inhaled bronchodilators and/or orally administered theophylline maintained or improved control of asthma symptoms and lung function relative to placebo. Long term studies indicate that the addition of nedocromil sodium to existing regimens which do not adequately control symptoms can improve asthma control and maintain improvement for the duration of the study without serious adverse effects. Addition of nedocromil sodium 4mg 4 times daily to existing therapy in patients receiving treatment with inhaled or oral corticosteroids has enabled a reduction in steroid dosage whilst maintaining control of asthma symptoms in some patients, although there was wide variation in the extent of steroid dosage reduction. Complete withdrawal of corticosteroids was possible in some patients after institution of nedocromil sodium, but the duration of these studies was insufficient to determine if disease stability can be maintained with substituted nedocromil sodium. Preliminary studies in children suggest that nedocromil sodium 16mg daily is more effective than placebo in controlling seasonal asthma. Further experience is required before the role of nedocromil sodium as maintenance therapy in young asthmatic patients can be defined. Further clinical experience with nedocromil sodium in the treatment of asthma has confirmed its good tolerability, with adverse effects being infrequent, mild, transient and seldom requiring withdrawal of treatment. Adverse effects most commonly reported include unpleasant taste (usually described as bitter), nausea, vomiting, sore throat, throat irritation, cough and headache, with other occasionally reported effects occurring with similar frequency in placebo and active drug recipients. The usual dosage of inhaled nedocromil sodium is 4mg 2 to 4 times daily in the treatment of adult and childhood asthma (12 years and older). Nedocromil sodium is indicated for regular maintenance therapy and not for relief of symptoms in an acute attack of asthma.