Nedocromil Research Articles

Mediator assays and modulation of inflammation in asthma: introduction.

The vital role of inflammation in the induction and perpetuation of asthmatic responses is now a widely accepted concept. Effective management of asthma requires modulation of asthmatic inflammatory responses. Eosinophils play a critical role in producing inflammation within the asthmatic lungs. Serologic assessment of the level of eosinophilic cationic protein (ECP) may be useful in assessing the degree of activation of eosinophils in asthma and the effect of pharmacotherapy on activated eosinophils. Several clinical trials have noted that ECP levels fluctuate in direct relationship to the amount of ongoing bronchospasm and asthmatic inflammation. Modulation of inflammation in asthma can occur through pharmacologic means. Nedocromil sodium has been demonstrated to significantly affect both early-phase and late-phase inflammatory events including effects on mast cell activation and effects on eosinophil function. Nedocromil sodium has also been noted to affect production and activity of cytokines that are vital to the perpetuation of the asthmatic late-phase response. Unlike cromolyn sodium, nedocromil sodium inhibits late-phase inflammation even when administered after the early phase of the allergic response and has also been demonstrated to be a steroid-sparing agent in mild-to-moderate asthmatics who require inhaled beclomethasone. Modulation of the metabolism of arachidonic acid, thereby affecting levels of prostaglandins and leukotrienes, may be extremely useful in selective asthmatic patients. Those patients having aspirin sensitivity and chronic rhinitis associated with asthma seem to be particularly responsive to arachidonic acid metabolites. In such patients, use of aspirin desensitization may be considered. Newer anti-inflammatory agents being investigated as treatments for asthma include methotrexate, hydroxychloroquin, auronifin, and sulfonylureas, among others.(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma symptoms and airway hyperresponsiveness are lower during treatment with nedocromil sodium than during treatment with regular inhaled albuterol

In a double-blind, double-dummy, multicenter study, 212 patients with asthma whose symptoms were not controlled by as-needed use of inhaled bronchodilators were randomized to receive either 4 mg of nedocromil sodium or 180 μg of albuterol four times daily for 12 weeks. Asthma symptom scores (daytime asthma, nighttime asthma, morning chest tightness, and cough) and peak expiratory flow rate were recorded daily on diary cards. Bronchial hyperresponsiveness was assessed by changes in diurnal variation in peak expiratory flow rate and by methacholine inhalation challenge. Statistically significant differences were found between groups favoring nedocromil sodium for relief of day and nighttime asthma and morning chest tightness. Patients treated with nedocromil sodium also had significantly lower diurnal variation in peak expiratory flow rate compared with patients treated with albuterol. Compared with patients treated with albuterol, patients treated with nedocromil sodium showed a greater improvement in cough and a decreased sensitivity to methacholine challenge. Patients in both groups reduced their as-needed albuterol use. Regular treatment with nedocromil sodium therefore led to greater asthma symptom control and reduced bronchial responsiveness compared with regular treatment with albuterol. The study also showed that more frequent use of a β2-agonist (for symptom relief or not) did not improve asthma control. Both drugs were well tolerated. (J A LLERGY CLIN I MMUNOL 1995;95:541-7.)

Nedocromil sodium and sodium cromoglycate inhibit plasma extravasation in the guinea-pig conjunctiva

Nedocromil sodium (NS) and sodium cromoglycate (CS) (both applied locally into the conjunctival sac) reduced in a dose dependent manner plasma extravasation induced by topical bradykinin and by topical substance P (SP), NS being approximately ten times more potent than CS. Plasma extravasation induced by SP was unaffected by the histamine H(1) receptor antagonist, pyrilamine, which completely blocked the plasma extravasation induced by histamine. NS and CS reduced the plasma extravasation caused by the mechanical stimulation of the conjunctiva, a response that was not affected by the tachykinin NK(1) antagonist CP-(99.994). NS or CS did not affect the contraction of strips of the guinea-pig trachea in vitro caused by SP in the presence of the tachykinin NK(2) receptor antagonist SR-(48968). NS, more potently than CS, reduces the plasma extravasation caused by various inflammatory stimuli in the guinea-pig conjunctiva, without inhibiting tachykinin NK(1) receptors, but probably by acting at the level of the venular endothelium. However, an inhibitory action of NS and CS on neural transmission of sensory nerves cannot be excluded.

Nedocromil sodium reduces cigarette smoke-induced bronchoconstrictor hyperresponsiveness to substance P in the guinea-pig.

Acute exposure to cigarette smoke provokes airway hyperresponsiveness to substance P and inactivates neutral endopeptidase (NEP). To determine whether nedocromil sodium can prevent cigarette smoke-induced hyperresponsiveness to substance P, we studied two groups of anaesthetized guinea-pigs. One group of guinea-pigs was pretreated with aerosolized 0.9% NaCl solution (90 breaths), the other group was pretreated with aerosolized nedocromil sodium (10(-4) M, 90 breaths). In each animal, pretreatment was followed by either exposure to the smoke of one cigarette or exposure to air. After acute exposure to cigarette smoke or to air, we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P. In the absence of nedocromil sodium, the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea-pigs than in air-exposed animals. Aerosolized nedocromil sodium had no effect on the response to substance P in air-exposed animals, but it reduced cigarette smoke-induced hyperresponsiveness to substance P. The preventive effect on cigarette smoke-induced hyperresponsiveness to substance P was observed at concentrations of aerosolized nedocromil sodium of 3 x 10(-5), 10(-4), and 3 x 10(-4) M. In vitro, cigarette smoke solution inhibited NEP activity from lung membrane preparations, but this inhibitory effect was not modified by nedocromil sodium (10(-4) M). We conclude that aerosolized nedocromil sodium reduces cigarette smoke-induced airway hyperresponsiveness to substance P in vivo. This action of nedocromil sodium is not due to a protective effect on cigarette smoke-induced inactivation of NEP in vitro.

NSAIDs in the Treatment of Adult Asthma: Sodium Cromoglycate and Nedocromil Sodium

Among nonsteroidal anti‐inflammatory drugs used in the treatment of adult asthma, sodium cromoglycate and nedocromil sodium are the most frequently prescribed. These medications have a similar efficacy profile in asthma although it has been suggested that nedocromil is more powerful than cromoglycate, particularly in its steroid sparing effects. Both drugs have been recommended as alternatives to steroids in the treatment of mild asthma. They are useful in the prevention of bronchospasm induced by exposure to allergens or to a variety of other stimuli. In comparison with theophylline or low dose inhaled steroids, cromoglycate and nedocromil have shown a similar antiasthmatic efficacy, although this is variable among patients.

Pharmacologic modulation of Th1 and Th2 cell subsets by nedocromil sodium.

Pharmacologic modulation of Th1 and Th2 cell subsets by nedocromil sodium.

Use of solid-phase extraction cartridges with differential-pulse cathodic stripping voltammetry at a hanging mercury drop electrode: determination of nedocromil sodium and pentamidine isethionate in urine

Nedocromil sodium (an antiasthma drug) and pentamidine isethionate (an antiprotozoal agent) were determined in urine by cathodic stripping voltammetry after adsorptive accumulation at a hanging mercury drop electrode as examples of the use of solid-phase extraction cartridges with this technique. Prior separation from matrix interferents was necessary and this was carried out using either a C18 solid-phase extraction cartridge or liquid–liquid extraction. For nedocromil, a recovery of 100.5 ± 6.5%(± 2 standard deviations) was obtained from urine spiked with 0.42 µg ml–1 of the drug using a C18 cartridge (five determinations). A 97% recovery of pentamidine isethionate was obtained by solid-phase extraction when the drug was added to urine at a level of 1.48 µg ml–1. At lower levels of pentamidine isethionate, better recovery was obtained using liquid–liquid extraction: recoveries of between 60 and 100% were obtained at levels of 0.04–29.6 µg ml–1. Linear calibration graphs were obtained for the determination of both drugs at concentration levels in the measured solution lower than 1 × 10–7 mol l–1(i.e., less than approximately 0.05 µg ml–1): standard additions method was preferred for quantification. Relative standard deviations of 4.5% for the determination of pentamidine isethionate and of 5.2% for the determination of nedocromil (n= 5) were obtained for urine samples containing 2.96 µg ml–1 of pentamidine isethionate and 0.42 µg ml–1 of nedocromil.

Nonsteroidal Anti‐Inflammatory Agents in the Treatment of Asthma in Children

The increasing scientific information clearly demonstrates the important role of inflammation in asthma. This evidence has led physicians to focus their treatment on the elimination of inflammation instead of working solely against bronchoconstriction. Steroids and nonsteroidal agents are currently used to prevent this inflammatory component. This paper focuses only on nonstcroidal anti‐inflammatory agents such as sodium cromoglycate, nedocromil sodium and ketotifen and their use in pediatric asthma. The discussion on each medication addresses its mechanism of action, the evidence concerning its efficacy in pediatrics (ie, clinical pharmacology, acute bronchial challenge, late asthmatic response, bronchial hyperrcactivity, clinical efficacy) and the pediatric dose.

Inhibitory effects of nedocromil sodium on cytokine production from mast and epithelial cells.

Inhibitory effects of nedocromil sodium on cytokine production from mast and epithelial cells.

Role of chloride channel modulation in the mechanism of action of nedocromil sodium.

Role of chloride channel modulation in the mechanism of action of nedocromil sodium.

The pathophysiology of ocular allergy: current thinking.

Seasonal allergic conjunctivitis is the only ocular disease to involve solely Type-1 hypersensitivity, the other main forms of ocular allergy--perennial allergic conjunctivitis, vernal and atopic keratoconjunctivitis and giant papillary conjunctivitis--each having a more complex immunological basis and a chronic inflammatory component. Involvement of secondary inflammatory cells, particularly eosinophils, in addition to the mast cells resident in the conjunctival substantia propria, can lead to more serious corneal damage with vision-threatening potential. Thoughtful management of allergic conjunctivitis is needed in order to control the ocular inflammation without incurring steroid-induced side-effects, and patient education is also an important factor in maintaining optimal allergen avoidance, especially in the more severe and chronic cases. Laboratory models can be helpful in assessing the potential of new drugs, and SWR mice (topically sensitised and challenged with short ragweed) show clinical signs of allergic conjunctivitis, together with mast cell and eosinophil involvement, remarkably similar to the human pathophysiology. The antiinflammatory activity of both steroids and nedocromil sodium observed in this animal model supports therapeutic evidence of the usefulness of second-generation mast cell stabilising drugs in the treatment of ocular allergy.

Asthma

Asthma is characterized by inflammation, reversible airway obstruction, and increased airway responsiveness to various stimuli. It has received wide public attention in recent years because of increasing morbidity and deaths, particularly among black persons. The important role of inflammation in the immunopathogenesis of asthma has led to a newer therapeutic approach directed at interrupting this inflammatory process. Among immune regulatory pathways involved in asthma pathogenesis, two lymphokines appear to be particularly important in controlling IgE production. Interleukin-4 is required for IgE production; without it, IgE production is inhibited. Interferon-gamma can diminish cell priming for interleukin-4 production. Thus, the interplay of these two cytokines will determine whether cells that can make interleukin-4 will be produced and, therefore, whether IgE will be produced in response to allergic stimuli. Further, in response to appropriate stimuli, mast cells and eosinophils are attracted to airways and release cytokines, lipid mediators, and preformed substances that cause inflammation. Modern asthma treatment is directed at interrupting this inflammatory process and places a much greater emphasis on use of anti-inflammatory agents, such as aerosolized or parenteral corticosteroids, and on non-steroidal anti-inflammatory agents, such as cromolyn sodium and nedocromil sodium. Research advances without therapeutic application, however, limit success. Projects such as the National Institute of Allergy and Infectious Diseases' National Cooperative Inner-City Asthma Study, which is directed toward underserved populations, are intended to identify more clearly the factors responsible for increasing morbidity and to develop appropriate therapeutic interventions.

Role of interleukin‐5 in enhanced migration of eosinophils from airways of immunized guinea‐pigs

1. Platelet activating factor (PAF), leukotriene B4 (LTB4) and interleukin-5 (IL-5) are potent chemoattractants for guinea-pig eosinophils, which may be involved in eosinophil recruitment and up-regulation in allergic diseases. Eosinophils from the bronchoalveolar lavage fluid (BALF) of ovalbumin-sensitized guinea-pigs were collected 24 h after antigen provocation and migration induced by PAF, LTB4 and rhIL-5 was studied. 2. Total BALF content and distribution of eosinophils were greater in immunized, ovalbumin-challenged guinea-pigs (5.0 +/- 0.8 x 10(6)/guinea-pig; 12 +/- 1%) than in immunized, saline-challenged animals (3.0 +/- 0.7 x 10(6)/guinea-pig; 7 +/- 1%). 3. The chemoattraction of eosinophils isolated on a metrizamide gradient was studied in micro-Boyden chambers, results being expressed as the number of migrating cells (mean +/- s.e. mean). PAF and LTB4-induced migration of eosinophils from immunized and OA-challenged guinea-pigs were significantly enhanced, as compared to immunized and saline-challenged animals (170 +/- 36 vs 35 +/- 9 migrating eosinophils for 10 nM PAF; 271 +/- 60 vs 110 +/- 19 for 1 nM LTB4). 4. The IL-5 antibody TRFK-5, in vivo, reduced eosinophil recruitment in BALF of antigen-challenged immunized animals as well as the enhanced responsiveness of eosinophils from the challenged animals, suggesting a role for IL-5 in the priming of eosinophils in vivo. 5. In contrast to TRFK-5, nedocromil sodium reduced to a similar extent eosinophil, macrophage and lymphocyte recruitment into the BALF of antigen-challenged, but failed to down-regulate the enhanced responsiveness of eosinophils from the challenged animals. 6. The increased eosinophil content in lungs from antigen-challenged guinea-pigs is thus selectively reduced by the anti-IL-5 antibody, which also attenuates the concomitant enhancement of the eosinophil responsiveness, supporting the concept that IL-5 is essential for recruitment and priming of eosinophils in vivo. In contrast, nedocromil sodium reduced non-selectively the total cell recruitment to the airways,but failed to attenuate the enhanced responsiveness of those eosinophils which migrated, indicating that its effects involve a different target.

Comparison of the protective effects of cromolyn sodium and nedocromil sodium in the treatment of exercise-induced asthma in children

Seventeen children with asthma were studied in a double-blind, crossover, placebo-controlled study designed to compare the efficacy of cromolyn sodium with that of nedocromil sodium in preventing exercise-induced asthma. All drugs were delivered through a metered-dose inhaler (cromolyn sodium, 10 mg; nedocromil sodium, 4 mg; placebo, two puffs). Nedocromil sodium and cromolyn sodium provided significant, comparable protection from exercise-induced asthma, and both drugs were better than placebo. We conclude that nedocromil sodium and cromolyn sodium administered by a pressurized aerosol provide equal protection against exercise-induced asthma in children.

Effect of sodium nedocromil on histamine release and toxicity induced by adriamycin

It has been proven that the anthracyclines induce an important, noncytotoxic histamine release from rat peritoneal mast cells. In this study we showed that sodium nedocromil significantly limits, in a dose-dependent manner, the release of histamine induced by adriamycin; in addition, the antiallergic drug reduces the cellular uptake of adriamycin in mast cells. Nedocromil sodium closely resembles sodium cromoglycate in its action on mast cells, but is superior to sodium cromoglycate in limiting both histamine release and adriamycin uptake. Extension of the preincubation time with sodium nedocromil decreased the inhibitory effect on histamine release and adriamycin uptake; this phenomenon has been recognized as a characteristic property of the chromones and related drugs. When injected before adriamycin administration, sodium nedocromil significantly improved the survival time of mice that were acutely or chronically treated with the antineoplastic drug. These results again indicate that histamine release could play a role in anthracycline toxicity.

Nedocromil reduces need for ??2-agonists

Nedocromil reduces need for ??2-agonists

A double-blind study of the efficacy of nedocromil sodium in the management of asthma in patients using high doses of bronchodilators

The effects of nedocromil sodium were assessed in 110 patients with asthma who experienced asthma symptoms despite the use of high doses of inhaled bronchodilators. During the baseline period, antiinflammatory agents were not permitted, and patients were treated with inhaled β-agonists on an as-needed basis. Patients who required 12 or more puffs of albuterol and experienced continuing asthma symptoms for 7 of the 14 baseline days were randomized to treatment groups. Subjects received either nedocromil sodium (4 mg) or placebo four times a day for 10 weeks. Statistically significant (p < 0.05) between-treatment differences (weeks 3 to 10), favoring nedocromil sodium, were determined for the asthma summary score, daytime asthma severity, asthmatic cough, morning peak flow rates, reduction of as-needed bronchodilator use, physician's assessment of asthma severity, and patient and physician opinions of treatment effectiveness. By trial end (week 10), sleep difficulty caused by asthma decreased 29% in the nedocromil sodium group and 4% in the placebo group (p = 0.006). Nedocromil sodium was well tolerated and improved asthma control while reducing the inhaled bronchodilator load of these patients with moderately severe asthma. (J ALLERGY CLIN IMMUNOL 1994;94:473-81.)

LCB 2183 inhibits the inflammation associated with oxazolone-induced contact sensitivity

LCB 2183, an anti-allergic and potential anti-asthma compound, has been investigated for its ability to inhibit contact sensitivity in the mouse. The delayed response to epicutaneous hapten challenge in this model is a classical T-cell-mediated inflammatory reaction which is dependent on an early initiation phase. Both the early and late components of oxazolone-induced contact sensitivity were inhibited by oral administration of LCB 2183 in a dose-dependent manner. The drug appears to act on the efferent limb of the response since administration before hapten challenge was effective, while administration before the initial sensitization was not. LCB 2183 acts early in the cascade of events leading to inflammation, since the initiation phase of the response was inhibited; nonetheless, an effect of the drug on the late acting inflammatory cells cannot be ruled out. In comparison with oral prednisolone, which was also able to inhibit both the early and late components of the response, LCB 2183 was less active. Sodium cromoglycate and nedocromil sodium, which are poorly absorbed from the gastrointestinal tract, were tested by intraperitoneal administration. Neither of these agents significantly altered the delayed response and only nedocromil sodium had a limited inhibitory effect on the early initiation phase. Thus, in this model, LCB 2183 demonstrated more anti-inflammatory potential and resembled prednisolone more closely than either nedocromil sodium or sodium cromoglycate. The possible relevance of these effects in relation to the inflammation which characterizes human asthma is considered.

Regional deposition of nebulized hypodense nonisotonic solutions in the human respiratory tract.

Deposition of nonisotonic therapeutic and diagnosis aerosols can cause changes in airway fluid composition and bronchoconstriction in sensitive subjects. "Hypodense" aerosols containing a relatively low concentration of droplets in the carrier air were used in the studies of regional deposition of radiolabelled nebulized solutions of hypo- and hypertonic saline, in order to investigate whether the number of droplets per volume of carrier can affect deposition. Solutions with and without 0.5% nedocromil sodium were nebulized in order to examine the effects of a potential modifier of the rates of heat and mass transfer. The deposition was quantified using penetration index (PI) calculated from images obtained by single photon emission computerized tomography (SPECT) in 11 healthy volunteers per study. There was an increase in the penetration index (10.9%, for the saline only; 15.5%, for the nedocromil study) of the hypotonic compared to the hypertonic aerosol, although the initial size distribution of both types of aerosols was very similar (mass median aerodynamic diameter (MMAD) 3.7 and 3.8 microns; geometric standard deviation (GSD) 1.8 and 1.5 for the hypo- and hypertonic aerosols, respectively). The present results confirm the effects of tonicity on deposition of aerosols found in a parallel study reported in this issue of the Journal. They also give support to the theory that, in addition to the concentration of the nebulized solutions, the number of droplets per volume of the carrier air is a factor affecting deposition of aqueous aerosols. The presence of 0.5% nedocromil sodium in the solutions did not appear to interfere with the processes of heat and water transfer in the airways.

High-dose nedocromil sodium as an addition to inhaled corticosteroids in the treatment of asthma

In a double-blind placebo-controlled trial nedocromil sodium in a dose of 8 mg four times daily or matching placebo was added to the treatment of 29 asthmatic patients. All patients were taking inhaled corticosteroids in a dose of up to 1000 micrograms daily. The trial agents were given for 6 weeks after a 2-week run-in period. Twenty-four patients completed the study, three withdrew because of adverse effects, two on placebo. Daytime asthma symptoms were significantly reduced on nedocromil compared to placebo (-0.46 vs. +0.09, P = 0.03). Night-time asthma and morning tightness were not changed significantly. Bronchodilator use in the night and day were lower on nedocromil but the differences were not significant. Morning peak flow rates were higher on nedocromil (+22.2 vs. +0.08, P = 0.06) and physicians opinions of overall effectiveness favoured nedocromil (U = 35.0, P = 0.04). These results confirm that nedocromil sodium may be a useful addition in asthma to low to medium doses of inhaled corticosteroids. The effects of 32 mg nedocromil daily were comparable to previous reports with lower doses.