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Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with an extremely low survival rate. It is characterized by a chronic inflammatory process with intense mast cell infiltrate that is associated with reduced survival. The aim of this study was to test the hypothesis that mast cells have an enhancing effect on NSCLC proliferation. To assess the tumor-promoting potential of mast cells, we used the human alveolar basal adenocarcinoma (A549) and the mouse Lewis lung carcinoma (LLC) cell lines, umbilical cord blood-derived mast cells (CBMC) and the mast cell-deficient mouse Sash model. The proliferation rate of A549/LLC cells was markedly increased by mast cells and histamine. Histamine proliferating activity was mediated via H(1), H(2) and H(4) receptors and caused ERK phosphorylation. LLC induced in Sash mice or in wild-type mice treated with the mast cell stabilizer nedocromil sodium displayed an accelerated growth (number of metastic colonies in the lungs, total lung area and lung/total mice weight ratio). In summary, we have shown a significant effect of mast cells and histamine in enhancing NSCLC/LLCX growth in vitro, while in a mouse LLC model in vivo we have found that mast cells are important negative regulators of cancer development. Therefore our results would indicate a pro-tumorogenic effect of the mast cells in vitro on established lung tumor cell lines, and anti-tumorogenic effect in mice at lung cancer induction. In conclusion, mast cell/anti-histamine targeted therapies should carefully consider this dual effect.

BACKGROUND: The preventive use of medications has been proposed to be effective in the treatment of seasonal rhinitis. OBJECTIVE: To evaluate the efficacy and safety of mometasone furoate and nedocromil sodium nasal sprays as prophylactic treatment for moderate to severe seasonal allergic rhinitis (SAR). PATIENTS: Sixty-one patients were recruited from 3 referral allergy centers. Inclusion criteria were history of SAR for 2 years or longer, sensitization to relevant local pollen (grasses, Parietaria, and olive), and age older than 12 years. METHODS: An open-label, randomized, parallel-group, "real-life" study design was used. Patients received mometasone furoate nasal spray once daily or nedocromil sodium nasal spray 3 times daily starting 2 to 4 weeks before the pollen season and continuing for up to 4 months. Instructions regarding the use of additional medications were given. Diary cards recording symptoms, use of medication, and adverse events were kept by the patients. RESULTS: All 61 patients completed the study. The prophylactic use of mometasone furoate vs nedocromil sodium led to significantly more days without symptoms (75.1% vs 54.5%; P < .001). The mometasone furoate group also had lower nasal symptom scores (mean, 1.4 vs 2.9; median, 0 vs 2; P < .001) and was more satisfied (93.1% vs 43.5%; P < .001). No serious adverse event was recorded, and there was no difference between the treatments in any adverse event. CONCLUSIONS: Prophylactic administration of mometasone furoate before the pollen season is safe and may lead to improved control of SAR compared with the use of nedocromil sodium.

The conventional model-fitting approach to kinetic analysis assumes a fixed mechanism throughout the reaction and therefore may be too simplistic for many solid-state reactions. Even for a reaction with a fixed mechanism, model fitting sometimes cannot identify the reaction model uniquely. The alternative model-free approach is sufficiently flexible to allow for a change of mechanism during the course of a reaction and therefore provides a more realistic treatment of solid-state reactions kinetics. The application of model-free analysis to solid-state dehydrations was investigated using the two consecutive dehydration reactions of nedocromil sodium trihydrate. The complexity of such reactions is illustrated by the variation of the activation energy as each dehydration proceeds. The 1st-step dehydration follows one-dimensional phase boundary kinetics until the fraction dehydrated reaches 0.75, and deviates from this model thereafter. The 2nd-step dehydration follows a mechanism intermediate between two- and three-dimensional diffusion that cannot be described by any of the common models. The model-free approach is clearly better than the model-fitting approach for understanding the details of these solid-state dehydration reactions.

Ketotifen fumarate 0.025% ophthalmic solution and nedocromil sodium 2.0% ophthalmic solution are 2 topical antiallergic medications with different modes of action and efficacy profiles. Both solutions are indicated for ocular itching associated with allergic conjunctivitis.This study compared the efficacy, safety, and comfort of ketotifen fumarate 0.025% ophthalmic solution and nedocromil sodium 2.0% ophthalmic solution for the prevention of ocular itching, using the conjunctival allergen challenge (CAC) model.This was a single-center, double-masked, contralateral, randomized, placebo- and active-controlled CAC clinical trial. Subjects aged10 years with a history of allergic hypersensitivity who responded to the CAC at screening visits 1 and 2 qualified for randomization at visit 3. At visit 3 (day 21) and visit 4 (day 35), subjects received 1 of 3 treatments: ketotifen, nedocromil, or placebo (artificial tears), randomized by eye. Allergen challenges were conducted at 5 minutes posttreatment dose (visit 3) and 12 hours posttreatment dose (visit 4). At each visit, subjects evaluated their ocular itching every 30 seconds for 20 minutes. At visit 4, subjects evaluated the comfort of the medication immediately after instillation, at 30 seconds after instillation, and at l, 2, 5, and 10 minutes after instillation. The subjects were also queried about overall eyedrop comfort by choosing from descriptive terms and about overall eyedrop preference based on comfort and perceived efficacy.Eighty-five subjects were screened for this study. Fifty-nine (28 males, 31 females; mean age, 38.7 years) qualified and were randomized to receive study medications. Ketotifen-treated eyes experienced significantly less ocular itching induced by CAC than nedocromil-treated eyes and those that received placebo at both the 5-minute and 12-hour posttreatment allergen challenges (all P0.05). Nedocromil-treated eyes showed no statistical or clinical differences from placebo at any time point. Ketotifen-treated eyes showed no differences in comfort from those that received placebo but were significantly more comfortable than nedocromil-treated eyes at 1, 2, 5, and 10 minutes after instillation (all P0.05). On the basis of comfort and subjective efficacy, 60% of subjects preferred ketotifen, 21% preferred nedocromil, and 19% preferred placebo.Ketotifen was significantly more effective and comfortable than nedocromil at both 5 minutes and 12 hours after administration in this CAC model.

In asthmatic children with persistent symptoms, maintenance therapy with nedocromil sodium, inhaled corticosteroids, or montelukast is associated with a decreased rate of asthma exacerbations. The greatest benefit is seen with use of regular inhaled corticosteroids in preschool- or school-age children, in whom asthma exacerbations, the need for rescue oral corticosteroids, unscheduled urgent medical visits, and hospitalizations are all decreased by approximately 50%. However, maintenance therapy is not beneficial in children with intermittent respiratory virus-induced wheezing without persistent symptoms. (J Pediatr 2003;142:S21-S25)

Background: Airway inflammation plays a central role in the pathogenesis of asthma, even in the mildest forms and at the earliest stages. Therapeutic strategies now aim to relieve bronchoconstriction as well as focus primarily on controlling the underlying inflammatory process. Clinical trials of children and adults with asthma have demonstrated that inhaled corticosteroids and cromones (such as nedocromil sodium [NS]) improve symptoms and lung function, as well as decrease nonspecific bronchial hyperresponsiveness. Objective: The aim of this study was to compare the effects of various anti-inflammatory therapeutic regimens using inhaled fluticasone propionate (FP) and/or NS on airway hyperresponsiveness to methacholine. Methods: Patients with mild, persistent asthma, who tested positive to a Dermatophagoides pteronyssinus skin prick test, were randomly assigned to 1 of 4 treatment groups: (1) FP for 16 weeks; (2) FP for 8 weeks, followed by NS for 8 weeks; (3) NS for 8 weeks, followed by FP for 8 weeks; or (4) NS for 16 weeks. Each patient was evaluated every 4 weeks. Results: Thirty-two patients with asthma (16 men and 16 women; age range, 18–48 years) were included in the study; 8 patients were randomly assigned to each of the 4 treatment groups. During treatment with FP alone, the provocative dose of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second (PD 20 ) was significantly higher than that recorded during treatment with NS alone (P 20 versus baseline values throughout the study. Moreover, when FP was administered as the second drug (after NS), a further increase in PD 20 compared with the values at week 8 occurred at both week 12 ( P P 20 decreased significantly compared with week 8 ( P P Conclusions: Our results suggest that, in this limited population of asthmatic patients who were treated for 16 weeks, FP was effective in increasing the PD 20 and that NS exerted an effective, progressive protective action against bronchial hyperresponsiveness to methacholine, thereby partially limiting the negative consequences of FP withdrawal on airway inflammation.

Inhalation of ultrasonically nebulised distilled water (fog) induces cough; however, the receptor type(s) mediating this reflex are poorly defined. In humans, cough threshold can be determined by inhalation of progressively increasing fog concentrations; the intensity of the associated motor response can be indexed in terms of flow-related variables as well as of the peak and slope of the integrated electromyographic activity of the abdominal muscles. We have evaluated coughing in patients with Parkinson's disease who show a high incidence of serious chest infections. These patients turned out to have a normal cough threshold but reduced expiratory muscle force during reflex coughing; this suggests an impairment in the central mechanisms subserving muscle activation possibly leading to inefficient airway clearing. Recurrent chest infections also affect laryngectomised patients. These patients have a normal cough threshold but reduced muscle force during coughing in response to threshold stimuli. Voluntary coughing is preserved in these patients, and this should be used to facilitate mucus removal. In normal subjects, fog inhalation causes cough and increases in respiratory drive and minute ventilation, mainly accounted for by increases in tidal volume, possibly due to activation of airway rapidly adapting receptors. Nedocromil sodium administration increases cough threshold and attenuates the ventilatory responses. The assessment of sensory and motor components of coughing may represent a useful tool for those investigating cough in humans.

Nedocromil sodium and levocabastine are widely used for the treatment of ocular allergy, but their mechanisms of action are unclear.We sought to compare the efficacy and mechanisms of action of nedocromil sodium and levocabastine in reducing conjunctival symptoms after ocular allergen challenge.We performed a double-blind, placebo-controlled study in which 48 subjects were randomized to 3 groups to receive nedocromil sodium (2%), levocabastine (0.05%), or placebo eye drops twice daily for 2 weeks before ocular challenge with 10 microL of ryegrass extract. Symptoms and tear histamine and PGD(2) concentrations were determined before challenge and at 10, 20, 30, 60, 180, and 360 minutes after challenge. Bulbar biopsy specimens were taken at 6 and 24 hours after challenge to assess conjunctival inflammatory cell numbers, adhesion molecule expression, and mast cell-associated IL-4, IL-5, IL-6, IL-13, and TNF-alpha levels.Both drugs significantly reduced total symptom scores (P.05) at all times after challenge compared with placebo. Itching, hyperemia, and lacrimation were most affected. Nedocromil sodium treatment reduced tear concentrations of histamine (by 77%) and PGD(2) (by 70%) at 30 minutes after challenge (both P.05). In biopsy specimens nedocromil sodium reduced the number of 3H4-positive mast cells (purportedly the secreted form of IL-4) by 49% at 6 hours and 59% at 24 hours (both P.05). Levocabastine reduced intercellular adhesion molecule 1 expression by 52% at 6 hours and 45% at 24 hours (both P.05).Nedocromil sodium and levocabastine both reduced the conjunctival symptoms after ocular allergen challenge but appeared to work by different mechanisms. Nedocromil sodium reduced mast cell function, whereas levocabastine appeared to have primarily antihistaminic actions, although it also reduced the expression of intercellular adhesion molecule 1.

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of ∼1 μm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the “micronized” nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12–76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1160–1169, 2000

A six-stage model is proposed to describe the overall process of sorption of water vapor on and into anhydrous nedocromil sodium. The way in which temperature, pressure, and time affect the rate of reaction for each of the stages has been analyzed. Experimental data for the measured rates, where temperature, pressure, and time are variables, are compared with the predictions obtained from each of the six stages. The most useful comparator is a graphical representation of reduced time versus hydration rate. The theoretical equations presented as a shape analysis of the experimental curves show the process to have different controlling mechanisms in three temperature regions: up to 27 degrees C, hydration is controlled by a nucleation and growth mechanism; between 27 and 31 degrees C, the process is dominated by diffusion of water molecules into the crystal; and >31 degrees C, neither nucleation nor diffusion are controlling but some, as yet, undetermined physical processes.

The effect of the spacers (Fisonair, Breath-A-Tech, Volumatic and Nebuhaler) on the in vitro aerosol characteristics of two propellant-driven metered dose inhalers (MDIs), Tilade (nedocromil sodium) and Intal (disodium cromoglycate), was studied. The measurement was carried out on a Marple-Miller impactor operating at 30 l/min. Five actuations were collected for the drug assay. The results showed that Tilade (label claim 2 mg active per actuation) and Intal (label claim 5 mg active per actuation) generated aerosols with a fine particle mass (FPM, i.e. mass of particles 5 microm in the aerosol) of 0.34 mg (S.D. 0.01, n = 4) and 0.02 mg (S.D. 0.01, n = 4) per actuation, respectively. For both inhalers, large volume spacers increased (Fisonair > Nebuhaler > Volumatic) while small volume spacer (Breath-A-Tech) decreased the FPM. The FPM (per actuation) for Tilade with Fisonair, Nebuhaler, Volumatic and Breath-A-Tech was 0.52 (0.03), 0.45 (0.03), 0.41 (0.04) and 0.09 (0.04) mg, respectively, while for Intal the corresponding values were 0.41 (0.02), 0.32 (0.04), 0.28 (0.03) and 0.08 (0.01) mg. Thus, the fine particle mass can be either increased or decreased, depending on the spacer selected. In addition, all spacers significantly reduced the coarse particle (> or = 10 microm) mass, with Fisonair, Breath-A-Tech, Nebuhaler and Volumatic producing only 7.6, 0.4, 5.2 and 2.6, respectively of that from Tilade alone and 15.6, 0.7, 5.4 and 4.1%, respectively of that from Intal alone. The general trends for Tilade and Intal were similar but not quantitatively identical. The proper choice of spacers is therefore important for the optimal delivery of Tilade and Intal.

Matrix metalloproteinases (MMPs) are particularly potent in degrading basement membrane collagen associated with lung injury in inflammatory processes. We have investigated the effects of betamethasone, cyclosporin, and nedocromil on MMP2 and MMP9 activities, on TNF-alpha and IL-10 release, as well as on the recruitment of inflammatory cells in the bronchoalveolar lavage (BAL) fluid after aerosol administration of lipopolysaccharide (LPS) in mice. When mice were pretreated with betamethasone (5 mg/kg, po), MMP2 and MMP9 activities, TNF-alpha in BAL fluids, and the enhanced neutrophil number of LPS-exposed mice were reduced, whereas the level of IL-10 was increased. Pretreatment of mice with cyclosporin (10 mg/kg, po) did not significantly reduce MMP activities, but cyclosporin inhibited neutrophil recruitment, inhibited increase TNF- alpha and inhibited IL-10 decrease. Nedocromil sodium (30 mg/kg, ip) had no influence on the LPS-induced MMP activities, on neutrophil recruitment, or on IL-10 level, but this drug elicited a significant inhibition of TNF- alpha level. These results showed that treatment with the antiinflammatory drugs cyclosporin and nedocromil sodium did not lead to reduction of MMP release. However, since betamethasone reduced the LPS-induced pulmonary inflammation and production of MMPs, these results suggest that corticosteroids may decrease tissue remodelling associated with acute lung injury.

Second generation antihistamines (anti H1) are effective for seasonal and perennial rhinoconjunctivitis curative or preventive treatment in children. They are better tolerated than first generation drugs. They probably do not act specifically against asthma itself, but are nevertheless useful for relief of nasal obstruction, which is an asthmogenic factor frequently linked with bronchial asthma. The therapeutic relevance of oral ketotifen and inhaled chromones (sodium cromoglycate, nedocromil sodium) is unequally considered among pediatricians. However, their efficacy has been clearly demonstrated as a ground treatment in mild-to-moderate asthmatic children. Chromones are also useful in preventing exercise-induced asthma. Because of their low cost and the lack of potential side effects, and according to the guidelines established in 1997 by the National Heart, Lung and Blood Institute, they should be prescribed at first sight in these indications.

We have previously developed poly(l-lactic acid) (PLA) microspheres containing nedocromil sodium and beclomethasone dipropionate (BDP) for aerosolisation to the respiratory tract (El-Baseir, M.M., Phipps, M.A., Kellaway, I.W., Preparation and subsequent degradation of poly(l-lactic acid) microspheres suitable for aerosolisation: a physico-chemical study. Int. J. Pharm. 151 (1997) 145–153). In this study we have investigated the in vitro release kinetics of these two drugs from PLA microspheres and the deposition of the microspheres in an in vitro lung model (Andersen cascade impactor) following aerosolisation from a dry powder inhaler (Spinhaler®). The in vitro kinetics of drug release revealed a controlled release of nedocromil sodium over 8 days with a burst effect (27–60%, w/w) which varied with the particle size of the microspheres. For BDP entrapped in PLA microspheres, controlled release of BDP occurred over 6 days. BDP release was determined by measuring the shift in the phase transition temperature of dimyristoylphosphatidylcholine (DMPC) liposomes induced by partitioning of the steroid into the lipid bilayers. The residual poly(vinyl alcohol) used as an emulsifier in the production of the microspheres was < 7% (w/w). The in vitro deposition of the microspheres (1.00 ± 0.21 μm) containing BDP from a Spinhaler® to a cascade impactor at a flow rate of 60 l/min, resulted in 20% of the emitted dose deposited on stages corresponding to particles < 3 μm and approximately 42% < 5 μm.

Background and objectives Although cromones inhibit immediate bronchial responses to both allergen and nonspecific challenge, their effectiveness in treating nonatopic childhood asthma is unknown. We therefore investigated a possible effect of nedocromil sodium on bronchial hyprreactivity and asthmatic symptoms in a group of children receiving this drug for nonatopic asthma. Study design and methods A double-blind, placebo-controlled, randomized trial of two parallel groups was carried out in our pediatric respiratory disease clinic. Twenty children with mild, nonatopic asthma hyperreactive to fog-induced challenge were treated with inhaled nedocromil sodium 16 mg each day for 6 weeks (group N) or with a placebo (group P). Five girls and five boys (7 to 13 years of age) were randomly assigned to group N, and three girls and seven boys (aged 6 to 16 years) to group P. Symptoms and bronchodilator use were reported on diary cards. Ultrasonic nebulized distilled water PD 10 was measured administering increasing doses of nebulized distilled water (2.5, 5, 10, 20, and 40 L). Results Symptom scores were significantly affected by the active treatment. Baseline lung function was normal and remained unaltered after treatment with nedocromil sodium. Nonspecific reactivity was significantly reduced over time only in the active treatment group. Conclusions Nedocromil sodium can reduce the severity of asthmatic symptoms and nonspecific bronchial hyperreactivity at fog-induced challenge in children with stable, nontoxic asthma.

Both PAF (10 microM) and bradykinin (0.1-10 microM) increased lysozyme (from submucosal gland serous cells (+138 and +45% for PAF, 10 microM, and bradykinin, 1 microM, respectively) and albumin (mainly active epithelial transport; +387 and +108%) outputs into the ferret tracheal lumen in vitro and reduced the negativity of the potential difference (PD: -33 and -17%) across the trachea. Since PAF can cause bronchial smooth muscle hyperresponsiveness, we tested whether these effects were interactive, and if PAF would increase the actions of bradykinin. The bradykinin-induced lysozyme and albumin outputs were more than trebled and the PD change was enhanced by PAF, after the immediate secretory effects of the latter had returned to baseline. The secretory and PD responses to PAF were all prevented by the PAF-antagonist WEB 2086 and by a combination of the free-radical scavengers catalase and SOD, indicating that PAF may act on specific receptors to release free-radicals. Nedocromil sodium inhibited the increase in lysozyme and albumin outputs produced by PAF, but had no effect on the PD response. None of the tracheal responses to bradykinin was modified by WEB 2086, catalase and SOD, or nedocromil sodium. The secretory and PD hyperresponsiveness to bradykinin caused by PAF was prevented by WEB 2086 and by catalase and SOD. Nedocromil sodium greatly inhibited the lysozyme and albumin hyperresponsiveness but had no effect on the PD response. Thus PAF may release more than one type of radical which have differential effects on serous cells and albumin transport compared with PD; nedocromil sodium may act only against the radical causing the secretory effects.

Multiple ocular challenges or seasonal trials have demonstrated the efficacy of levocabastine and nedocromil sodium in the treatment of allergic conjunctivitis.This study was designed to compare the protective effect of levocabastine eye drops with that of nedocromil in a conjunctival provocation test with allergen.Twenty-four patients with allergic conjunctivitis to grass pollen were recruited. After a preliminary provocation to determine conjunctival reaction threshold (erythema of at least 50% of the conjunctiva with ocular itching), patients were randomized to receive either topical levocabastine (0.05%) or nedocromil (2%) 15 minutes before provocation. Erythema and pruritus intensity were recorded at each concentration of allergen up to the reaction threshold.The allergen concentration level necessary to reach reaction threshold was increased (p0.001) after treatment with both drugs. Comparison between screening and each treatment indicated that the shift in allergen concentration was significantly greater after levocabastine treatment than after nedocromil treatment (p = 0.019). Conjunctival itching (symptom score) and erythema (percent conjunctival surface) were also better controlled by levocabastine than by nedocromil during provocation (p0.05).In a provocation test with allergen, levocabastine and nedocromil were both effective in increasing the conjunctival tolerance to allergen, with better protection provided by levocabastine.

One of the aspects of asthma that has become increasingly evident in our discussions at this meeting is that, like other chronic inflammatory disorders, the disease appears to evolve. In very early childhood, viruses are a particularly important trigger, whereas in the school years and early teens, allergens play an increasing role as the immune response translates itself into atopy expressed in the form of asthma. Asthma may then emerge as a persistent disorder with episodes of exacerbation superimposed on a background level of inflammation. The triggers for these exacerbations may vary as the asthma progresses. As the disease becomes more severe and chronic it appears to acquire an increasing "intrinsic" component, in the sense that it becomes less dependent on common environmental agents. Moving into chronic persistent asthma in adulthood, it is possible to see how the T-cell repertoire of cytokines can take over and drive the progression of the disease and enroll the constitutive cells to bring about irreversible structural changes. By elucidating this evolution, we can explore the possibility of preventing that transition into a disease that is difficult to treat and manage. Numerous lines of evidence support a primary role for the mast cell early in the development of asthma. Mast cells, along with eosinophils and lymphocytes, are present in increased numbers in the airways of patients with asthma. Mast cell mediators are also increased in persons with allergies, with the concentrations of histamine, tryptase, and prostaglandin D 2 proportional to the degree of airway obstruction and bronchial hyperresponsiveness (BHR). Increased numbers of activated mast cells and eosinophils (but not T cells or macrophages) have also been found in

The airways of persons with asthma are sensitive to acute changes in airway osmolarity and to dehydration. In reviewing the literature it is clear that airway narrowing provoked by these stimuli is blocked acutely by inhaling aerosols of nedocromil sodium, cromolyn sodium, frusemide, bumetanide, and antihistamines and by chronic use of aerosol corticosteroids. The responses are unaffected by inhalation of amiloride and verapamil. We have previously proposed that increases in the osmolarity of airway surface liquid (ASL) occur as a result of the water lost by evaporation during hyperpnea with dry air. An increase or decrease in osmolarity of the ASL will also occur with deposition of hyperosmolar and hypoosmolar droplets. Changes in osmolarity of the ASL result in the movement of water out of (shrinkage) and into (swelling) the epithelial cell, and this necessitates regulatory volume increase or decrease by the cell. We propose that nedocromil sodium and cromolyn sodium can affect water transport into and out of the epithelial cell by an action on chloride ion channels. A unifying hypothesis to explain the protective effect of these drugs may be their capacity to affect regulatory volume increase or decrease in a variety of cell types.

Many studies have demonstrated the ability of nedocromil sodium to block the acute response to allergen in persons who are sensitive to allergen. One study with subjects sensitive to ragweed showed a significant protective effect after a single 4 mg dose of nedocromil sodium, with no further protection achieved at higher doses. Numerous studies have also shown the ability of the drug to reduce or abolish the late asthmatic response in sensitive subjects when it was given before allergen challenge. Nedocromil sodium has also been shown to prevent the subsequent development of bronchial hyperresponsiveness. In addition, nedocromil sodium prevented the late asthmatic response when given after allergen challenge and an intact early response. These findings suggest that nedocromil sodium may be preventing the inflammatory events initiated by mast cell mediator and cytokine release.

In many patients with asthma, exposure to allergen results in worsening symptoms, pulmonary dysfunction, and increased airway inflammation. In this study, segmental allergen challenge and bronchoalveolar lavage were used to evaluate the airway responses at 5 minutes and 48 hours and to study the extent of inhibition of the response by pretreatment with nedocromil sodium in eight subjects with allergic asthma in a double-blind, placebo-controlled trial. At 5 minutes after challenge, nedocromil sodium pretreatment significantly reduced histamine concentrations, with a trend toward a concomitant reduction in tryptase levels. Nedocromil sodium did not affect the increase in total protein, total cell counts, or cell concentrations that occurred 48 hours after challenge, but it did significantly reduce eosinophil recruitment. Eosinophil activation, assessed as release of granule proteins, was unaffected. A significant positive correlation was shown between the degree of histamine reduction at 5 minutes and the degree of reduction of eosinophil influx at 48 hours, raising the possibility that eosinophil influx into the airway may depend on mediators or cytokines released during the immediate response to allergen.

If cell numbers, activation state, or mediators, for example, can be correlated with some clinical measure of disease severity, a major effector role in the disease may be postulated. Mast cells, along with eosinophils and lymphocytes, are present in increased numbers in the airways of patients with asthma. Mast cell mediators are also increased in persons with allergies, with the concentrations of histamine, tryptase, and prostaglandin D2 being proportional to the degree of airway obstruction and bronchial hyperresponsiveness. Increased numbers of activated must cells and eosinophils (but not T cells or macrophages) were also found in bronchoalveolar lavage fluid in children. The mast cell is also known to release a range of cytokines (e.g., tumor necrosis factor-alpha and IL-4) that have various important functions, including upregulation of the endothelial adhesion molecules that are responsible for eosinophil recruitment from the microvascular circulation into the airways and subsequent activation. Mast cell staining for secreted IL-4 was found to be proportional to the infiltration of eosinophils and lower airway symptoms in patients with seasonal asthma, which is compatible with the concept that mast cells alone can sustain a continuing allergic inflammatory response. The mast cell proteases chymase and tryptase are also important for eosinophil recruitment and activation and for increasing mucus secretion and microvascular permeability. The evidence that the human mast cell is capable of releasing proteases and cytokines that have the capacity to initiate and maintain a chronic inflammatory response provides a mechanism whereby the clinical efficacy of nedocromil sodium in patients with chronic mild to moderate asthma can be explained.

Several lines of evidence support the central role of the cysteinyl leukotrienes in aspirin-sensitive asthma, although their cellular source is unknown. The two most likely cells are the mast cell and eosinophil. Compared with aspirin-tolerant patients with asthma, patients with aspirin-sensitive asthma have been found to have a greater infiltration of mast cells and eosinophils in bronchial biopsy samples, although proportions of activated eosinophils were similar. Findings that support the involvement of mast cells include elevated serum histamine and tryptase levels after aspirin challenge in sensitive subjects, in line with a decrease in lung function and increased histamine and leukotriene C 4 levels in nasal secretions; release of high-molecular-weight neutrophil chemotactic factor into serum after challenge; and prevention of aspirin-induced bronchoconstriction by pretreatment with cromolyn sodium or nedocromil sodium. These agents are also effective in protecting against bronchoconstriction induced by hyperosmolar stimuli, a challenge that is not associated with increased leukotriene E 4 responsiveness but that is followed by increased release of histamine and prostaglandin D 2 into bronchoalveolar lavage fluid. Antihistamines are poorly effective at inhibiting aspirin-induced bronchoconstriction but have been shown to attenuate the bronchoconstrictor response to hyperosmolar challenge. The main effector mechanism in hyperosmolar-induced bronchoconstriction appears to be mast cell activation and histamine release. (J ALLERGY CLIN IMMUNOL 1996;98:S67-72.)

Nedocromil sodium has been shown to be capable of inhibiting chloride ion flux in mast cells, epithelial cells, and neurons. This feature may explain how it can prevent responses such as mast-cell degranulation, the effects of osmolarity changes in the airways, and neuronal activation. This mechanism may also provide a unifying hypothesis to explain the effects of nedocromil sodium on a range of cell types involved in asthma, such as sensory and efferent neurons and cells involved in inflammation.

We have developed a guinea pig model that allows monitoring of single afferent nerve fiber activity after stimulation of tracheal nerve endings with various stimuli. Action potentials from nodose or jugular neurons are recorded extracellularly. Previous experiments have shown that the excitability of the nerve endings to, for example, mechanical stimuli can be increased by antigen challenge of presensitized guinea pigs. Nedocromil sodium 10(-4) mol/L significantly reduced by more than 50% the generation of action potentials in C fibers in response to stimulation by capsaicin. The precise mechanism is not known, although the membrane depolarization induced by capsaicin was reduced in the presence of nedocromil sodium. This agent did not have a generalized inhibitory effect on afferent excitability because it had no effect on sensitivity to electrical or mechanical stimuli. Nedocromil sodium did not affect the generation of action potentials in A delta and C fibers in the presence of hypertonic saline solution.

We conducted a series of studies investigating the antiinflammatory effects of nedocromil sodium, with particular reference to its effects on human bronchial epithelial cells and eosinophils in vitro and on eosinophils in vivo. Nedocromil sodium produced a dose-related inhibition of ozone-induced IL-8 release from human bronchial epithelial cells and also attenuated the release of granulocyte macrophage colony-stimulating factor, tumor necrosis factor-alpha, and soluble intercellular adhesion molecule 1. The culture medium from human bronchial epithelial cell cultures, containing the proinflammatory cytokines IL-8, granulocyte macrophage colony-stimulating factor, "regulated on activation, normal T expressed and secreted," IL-1 beta, and tumor necrosis factor-alpha, increased eosinophil chemotaxis and eosinophil adhesion to cultured human endothelial cells. The chemotaxis and increased adhesion were blocked in the presence of nedocromil sodium. The drug also abrogated the epithelial cell dysfunction (assessed as ciliary beat frequency) induced by the presence of activated eosinophils and blocked the release of eosinophil cationic protein from the eosinophils. We also conducted a double-blind placebo-controlled study of the effects of regular albuterol 200 micrograms or nedocromil sodium 4 mg, both given four times daily for 16 weeks, on inflammatory cell numbers in bronchial biopsy and bronchoalveolar lavage samples. Assessed in terms of total and activated eosinophils in biopsy samples, inflammation decreased with nedocromil sodium and was significantly different from a deterioration with albuterol, although neither of these changes was significantly different from that with placebo treatment. Levels of eosinophil cationic protein in bronchoalveolar lavage samples showed a similar trend.

This review cites clinical evidence demonstrating that nedocromil sodium can reverse the clinical features of airway inflammation in asthma, as shown by decreased bronchial responsiveness, decreased diurnal variation in peak expiratory flow, improved baseline lung function, and a decrease in the frequency and severity of chronic symptoms. Clinical trials have also shown that nedocromil sodium has a statistically significant and clinically relevant effect on daytime and nighttime asthma symptoms within 3 days of starting treatment. On an analysis of relevant trials, the effect on asthmatic cough was significant within 24 hours. This rapid effect on symptoms, together with a reversal of the underlying airways inflammation, is a beneficial combination in the management of asthma. (J ALLERGY CLIN IMMUNOL 1996;98:S143-50.)

Allergen exposures induce growth of airway smooth muscle in the Brown Norway rat.The purpose of the study was to examine the role of mediators associated with the early and late responses in the induction of airway smooth muscle growth.Nedocromil sodium was administered to block early and late responses in ovalbumin-sensitized and ovalbumin-challenged rats undergoing single or multiple challenges (5 times at 5-day intervals) with ovalbumin. Airway smooth muscle was quantitated by morphometry on lungs removed 2 days after the final challenge.Nedocromil sodium administered before ovalbumin challenge blocked both the early and late responses. When administered 2 hours after ovalbumin challenge, it also blocked the late response. Rats undergoing challenge with aerosolized ovalbumin five times at 5-day intervals were also treated with nedocromil before (n = 10) or 2 hours after (n = 10) each ovalbumin inhalation, respectively. The quantity of airway smooth muscle standardized for size was greater after ovalbumin challenge (0.069 +/- 0.005) compared with saline controls (0.033 +/- 0.003, p0.005). Nedocromil significantly reduced the airway smooth muscle (0.036 +/- 0.003, p0.005) when administered before ovalbumin. However, the airway smooth muscle in rats that received nedocromil 2 hours after ovalbumin challenge (0.046 +/- 0.003), although lower than in ovalbumin-challenged rats (p0.01), was still significantly higher than in saline-treated rats (p0.05).Allergen-induced early responses, late responses, and airway inflammation are antagonized by nedocromil. The mediators of both the early and late responses contribute to allergen-induced airway smooth muscle growth, a process that can be prevented by administration of nedocromil.

1. 1. The eosinophil is part of the host defence mechanism to parasitic infection, but is also a key cell in many inflammatory disorders. 2. 2. Eosinophils synthesise a range of pro-inflammatory and cytotoxic mediators, such as basic proteins, hydrolytic enzymes, lipid mediators, cytokines, oxygen metabolites and neuropeptides. 3. 3. Eosinophils are recruited to the lung during episodes of asthma. They migrate from the blood vessels into the tissue via a series of interactions between their surface adhesion molecules and endothelial cells or the extracellular matrix. 4. 4. Activation and prolonged survival of eosinophils occurs upon exposure to mediators released from other tissue resident leukocytes, including eosinophils themselves, and from respiratory tract epithelial cells. Release of eosinophilic mediators causes tissue damage and persistent inflammation of the lung. 5. 5. Currently the most effective therapy for asthma lies with anti-inflammatory drugs, of which the main choices are inhaled corticosteroids or cromolyn sodium and nedocromil sodium.

For many years, asthma has been classified as a "neural" disease, with an imbalance between constrictor and dilator nerves being responsible for the symptomatology. Although, nowadays, asthma is recognized as an inflammatory disorder of the airways, neural mechanisms remain very important; axon reflexes, in particular, have received a lot of attention in recent years. In this commentary, an overview is given on the innervation of the airways and its relevance in asthma, and potential new insights in airways innervation are discussed. In a second part, the role of axon reflexes is highlighted. Although neuropeptides such as substance P and neurokinin A are present in human airways, where they produce many of the features characteristic of asthma, and although there is an elevation of their content in induced sputum from asthmatics, there is still no clear direct evidence for the existence of operational axon reflexes in human airways. Most of the research focused on this subject is performed in guinea pigs, where such an axon reflex clearly operates in the airways. In these animals, different receptors have been identified on C-fiber endings, which, upon stimulation, cause inhibition of neuropeptide release. Some of these receptors have also been identified on human airway nerves. Therefore, it has been suggested that modulation of axon reflexes could be of potential benefit in asthma treatment. Indeed, some drugs (e.g. sodium cromoglycate, nedocromil sodium, and ketotifen), which have been demonstrated to partially inhibit neuropeptide release in guinea pig airways, have anti-inflammatory effects on neuropeptide release in guinea pig airways, do not seem to have any anti-inflammatory effects in human asthma. Other drugs, however, such as beta2-mimetics, which have a much more pronounced inhibitory effect in asthma. In conclusion, although there is a lot of indirect evidence for the existence of axon reflex mechanisms in human airways, most of the data now available are derived from animal studies. The key question of whether axon reflexes are operational in human airways remains unanswered. Hopefully, the near future will bring a solution to this enigma with the introduction of very potent tachykinin antagonists for the treatment of human asthma.

Nedocromil sodium and cromolyn sodium are the only two currently available nonsteroid anti-inflammatory agents for treatment of asthma. Clinical differences between the two agents remain under continuous investigation with reports differentiating the two on the basis of atopy of the patient and reversibility of bronchoconstriction. This study investigated the efficacy of nedocromil sodium (4 mg, qid) for treatment of mild-to-moderate asthma in comparison to placebo using cromolyn sodium (2 mg, qid) as an active control treatment. Patients were primarily allergic asthmatics (with at least 15% reversibility) previously maintained on a regimen of regular bronchodilator therapy. During a 2-week run-in period, the patient's slow-release theophylline therapy was removed, and the patients were randomized to treatment after deterioration of asthma control (asthma symptom summary score of 3 for 7 of the 14 days). After 8 weeks of treatment, patients were returned to as occasion requires bronchodilator therapy, as per the 2-week baseline period. The results demonstrate that patients treated with nedocromil sodium shewed statistically significant improvements during the primary time period (mean weeks 3 through 8) over placebo-treated patients as evidenced by all indexes of asthma symptoms, pulmonary function measures, and decreased bronchodilator reliance (p 1 , and forced expiratory flow rate between 25% and 75% of the FVC) in favor of cromolyn sodium when the data were pooled during the primary time period. The number of patients missing 1 or more days from work/school/regular activity due to asthma was significantly fewer compared with placebo, and favoring nedocromil sodium over cromolyn sodium. No differences were observed among the three treatments for adverse events. This study demonstrated that in primarily allergic patients with reversible airways disease, nedocromil sodium and cromolyn sodium are both significantly more effective than placebo for treatment of mild-to-moderate asthma.

Summary The synthesis and pharmacological profile of a series of 2-alkoxy and 2-phenoxymethyl-3 H -pteridin-4-ones and related compounds are described. These compounds displayed antiallergic activity in the passive cutaneous anaphylaxis test in rats. In contrast to both sodium cromoglycate and nedocromil sodium, many of our compounds were active when administered orally. The most potent in this series, 2-ethoxymethyl-3 H -pteridin-4-one 2b (LCB 2183) was investigated in other models of allergy and inflammation. The antiallergic activity was confirmed and interesting antiinflammatory properties were observed. It was therefore selected for further development as a human therapeutic agent.

Cromolyn sodium (10 mg), nedocromil sodium (4 mg), and placebo, all delivered by a metered dose inhaler, were compared in their efficacy and duration of action in preventing exercise-induced asthma in children. After a screening test was performed, 13 patients with asthma performed standard exercise tests 20 minutes and 140 minutes after drug inhalation in a randomized, double-blind, crossover study. Both drugs were significantly more protective than placebo after 20 minutes, but no significant difference was seen between cromolyn sodium and nedocromil sodium. No difference between active drugs and placebo was found 140 minutes after inhalation. At these clinically recommended doses both cromolyn sodium and nedocromil sodium provide equal protection against exercise-induced asthma, and the duration of action of both lasts for less than 2 hours.

Nedocromil sodium is commonly suggested to reduce allergic inflammation by inhibiting mediator release from mast cells. However, nedocromil also exhibits a wide range of additional anti-inflammatory activities, including inhibition of increased vascular permeability induced by individual mediators such as histamine. In the present study, we have further characterized the mode of action of nedocromil in a rat model for hind paw edema. Mast cell-dependent edema was induced with compound 48/80 (edema response mainly due to 5-hydroxytryptamine release), and direct mediator-induced plasma extravasation was evoked by exogenous 5-hydroxytryptamine (both agents injected locally). Local pretreatment with nedocromil for 20 min dose-dependently inhibited the edema evoked by compound 48/80 more effectively than that induced by 5-hydroxytryptamine. However, after 2 h pretreatment, both the 5-hydroxytryptamine-and compound 48/80-induced edema responses were inhibited to approximately the same extent by a range of concentrations of nedocromil, as well as by dexamethasone. Local inhibition of RNA/protein synthesis with actinomycin-D abolished the effects of both dexamethasone and nedocromil (2 h local pretreatment). We thus conclude that nedocromil can produce an 'anti-exudative' effect that is independent of inhibition of mast cell mediator release, is slow in onset, and requires de novo protein synthesis.

We have previously demonstrated that histamine release from immunologically activated mast cells (MC) is enhanced by their preincubation (1 h) with interleukin-2(IL-2), and that IL-2 induces slow-chronic histamine release by MC in long-term cultures (6 days). In the present study we assessed whether nedocromil sodium can interfere with IL-2 modulation of MC histamine release. IL-2 enhancing effects nedocromil sodium activity were studied in cocultures of rat peritoneal MC with 3T3 fibroblasts (MC/3T3). MC/3T3 were preincubated for 1 h with IL-2 (50 micrograms/ml) and activated with either rabbit anti-rat IgE or compound 48/80. In chronic experiments MC/3T3 were long-term (5-6 days) incubated with IL-2 (50 micrograms/ml). Nedocromil sodium was used at 10(-5) M. MC activation both when added during the preincubation period (no tachyphylaxis was present) and when added together with the MC activators (30-50% inhibition). Washing out IL-2 before addition of the anti-IgE antibodies did not affect its histamine-release enhancing activity. Removal of nedocromil sodium before addition of the stimulus completely abrogated its effect. Continuous presence of IL-2 in the culture medium enhanced spontaneous histamine release by 37% and this effect was completely abolished in the presence of nedocromil sodium. Furthermore, nedocromil sodium decreased MC basal histamine release by 23% in long-term cocultures. Since IL-2 is known to be elevated in some pathological conditions, our results show that nedocromil sodium inhibits MC activation in an in vitro system which may represent a close resemblance to the in vivo allergic response.

An automated HPLC method is described for the determination of nedocromil sodium in human urine. An HPLC autosampler is used to inject urine samples onto a short reversed-phase column. This column acts as a concentration column and performs a preliminary extraction. The concentration column is automatically back-flushed onto an ion-exchange column where final separation of nedocromil sodium from urine constituents occurs. Recovery, accuracy, precision, sensitivity and specificity were investigated. The method has been applied to urine samples from clinical studies, and the results were compared to those obtained using a radioimmunoassay developed previously.

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.

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.

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.

In a multicenter, double-blind, group comparative trial, the efficacy of nedocromil sodium (nedocromil, 4 mg, four times daily [ qid ]), cromolyn sodium (2 mg, qid ), and placebo was compared in patients receiving inhaled β 2 -agonists and inhaled corticosteroids for the treatment of chronic reversible obstructive airway disease. After a 2-week baseline period, 132 patients (8 centers) between the ages of 20 and 75 years entered a 4-week run-in period in which the dose of inhaled corticosteroid was reduced by 50 percent. During the run-in phase, deterioration of symptoms (total symptom score) by ten points qualified patients to enter the 6-week drug trial period. Patients in the nedocromil treatment group showed the most robust and consistent improvements over placebo and cromolyn sodium for all daily diary variables. Statistically significant improvements over placebo were noted for both active treatment groups for daytime, nighttime, and total symptom score. Symptom scores for nedocromil were statistically significantly improved over both cromolyn sodium and placebo for both daytime and nighttime asthma. Patients treated with nedocromil also demonstrated a significant reduction in the use of nighttime as needed ( prn ) β 2 -agonists as compared with either the placebo- or cromolyn sodium-treated groups. Only nedocromil-treated patients demonstrated a statistically significant improvement in morning peak expiratory Bow rate (PEFR) as compared with placebo. Both nedocromil and cromolyn sodium groups demonstrated statistically significant improvements in afternoon and evening PEFRs. Collectively, the improvements in nighttime symptoms, decreased bronchodilator use, and improved morning PEFR show that patients treated with nedocromil had improved nocturnal symptoms. Pulmonary function tests (FEV 1 , FVC, PEFR) demonstrated no statistically significant differences between the two active treatments, although trends favored nedocromil for both FEV 1 and PEFR. Although symptoms improved in patients treated with cromolyn sodium, the level of symptom control was less than that achieved by nedocromil. As compared with baseline control (regular dose of inhaled steroids), patients treated with nedocromil plus the 50 percent reduced dosage of inhaled corticosteroid consistently demonstrated comparable or better symptom control. Although both active drugs reduced symptoms, nedocromil proved to be more effective than cromolyn sodium for treatment of reversible obstructive airway disease in patients normally well maintained on regimens of low to moderate doses of inhaled corticosteroids.

Human monocytes, alveolar macrophages, and blood platelets were used in vitro to investigate the effects of nedocromil sodium on their IgE-dependent stimulation. The drug induced a significant inhibition of the IgE-mediated generation of cytotoxic mediators in both cell populations. This was evidenced by a strong inhibition of the killing of schistosome larvae and decreased free radical production, as demonstrated by chemiluminescence. Nedocromil sodium also produced a significant inhibition of lysosomal enzyme release and synthesis in alveolar macrophages. These effects reached a maximum between 10 −9 and 10 −7 mol/L nedocromil sodium. The 50% inhibition concentration was 10 times lower. The drug was also tested on IgE-activated rat peritoneal macrophages and blood platelets with similar results. Finally, nedocromil sodium was shown to inhibit the abnormal response to aspirin of platelets, both in vitro and ex vivo, from aspirin-sensitive asthma patients.

Although detailed histopathologic studies have described the inflammatory processes present in fatal asthma, until recently the pathology of less severe forms of the disease has been less well understood. Now a series of important studies has extended our understanding of the pathophysiology of mild asthma. Studies that examine sputum or fluid obtained by bronchoalveolar lavage from mildly asthmatic subjects revealed findings consistent with an active inflammatory process within the airways. The histopathologic examination of endobronchial biopsy specimens from stable asthmatic patients has shown that inflammatory cell infiltration of the mucosa is a distinctive feature of mildly asthmatic subjects requiring only intermittent inhaled beta-agonist therapy. These studies have also shown that marked tissue disruption may occur early in the natural history of mild asthma. These investigations have demonstrated that asthma is a disease characterized by acute and chronic inflammatory changes within the airways and that in many respects the histopathologic features of mild allergic asthma are similar to those observed in fatal asthma. The therapeutic implications of these findings are that management of mild asthma should be directed toward resolving this inflammatory process. There is now sufficient evidence to suggest that anti-inflammatory drugs such as cromolyn sodium, inhaled corticosteroids, and nedocromil sodium be used earlier in the course of the disease and that the use of these therapeutic agents should not be limited to patients with severe forms of asthma. This may be particularly important in view of the increasing awareness of the potential problems associated with the overreliance on beta-agonist therapy in patients with asthma.

Fourteen adult patients with bronchial asthma who were known late responders to bronchial allergen challenge were entered into a double-blind crossover study to compare the protective effects of nedocromil sodium (3 x 4 mg) and placebo aerosols on the late asthmatic response (LAR). After screening for development of an LAR (fall in forced expiratory volume in 1 second [FEV1]or = 20% at at least 3 consecutive time points, 4 to 10 hours after challenge), patients were randomized to test treatment on 2 study days, with an interval of at least 3 days. Nine of the patients had a dual late response, which is a combination of an immediate and a late response, and five other patients had an isolated late response only. On each study day the concentration of allergen that previously elicited a response was inhaled for 10 minutes. FEV1 was recorded every 10 or 15 minutes for up to 1 hour after challenge, and then at hourly intervals for 12 hours and every second hour on the next 2 days. Test treatments were administered in three doses at 30-minute intervals, with the first dose given 90 minutes before the expected onset of the LAR for each patient. Compared with placebo, nedocromil sodium significantly inhibited the LAR (p0.05) at each time point measured from 6 to 10 hours after challenge and reduced the maximum fall in FEV1 by 21.0% overall (p = 0.003).

We developed a model of asthma in conscious guinea pigs in which both early- and late-phase reductions in specific airways conductance are demonstrable after inhalation challenge. Neutrophilia that peaks 17 hours after challenge was discovered by bronchoalveolar lavage in this model, as was eosinophilia that develops more slowly, peaking at 72 hours. Nedocromil sodium blocked both the early- and late-phase reductions in airflow, but salbutamol blocked only the early phase. Both drugs blocked the neutrophilia when given before challenge, but not when given 6 hours afterward. This suggests that the neutrophilia is secondary to an intact early phase response. Nedocromil sodium, given 6 hours after challenge, reduced the eosinophilia at 72 hours but not at 17 hours. Salbutamol had no effect on the eosinophilia at either time. These results suggest that nedocromil sodium has antiinflammatory properties in the lung that are not shared by the β 2 -adrenergic stimulant drug, salbutamol.

This study evaluated the airway effects of nedocromil sodium in the sheep model of allergic bronchoconstriction. Nedocromil sodium provided statistically significant protection against both reflex- and mediator-induced bronchoconstriction in allergic sheep as assessed by bronchial responses to inhaled bradykinin and platelet-activating factor, respectively. When administered before antigen challenge, nedocromil sodium blocked both the immediate and late asthmatic response and prevented the subsequent increase in airway hyperresponsiveness. The protective effect of nedocromil sodium against the antigen-induced late response was associated with a significant decrease in the number of airway eosinophils measured by bronchoalveolar lavage. Although nedocromil sodium has no direct bronchodilatory activity, it prevented antigen-induced contractions in sheep tracheal smooth muscle in vitro. These results suggest that nedocromil sodium is active in the sheep model of allergic bronchoconstriction and may be useful in the treatment of reversible obstructive airway disease in human beings.

Clinical trials reported in these proceedings have shown that nedocromil sodium is an effective antiasthmatic agent. Preclinical studies and the results of the worldwide clinical study program have also shown that nedocromil sodium is a very safe drug. Although it is anticipated that a new drug will perform better than placebo, perhaps a more critical assessment of efficacy is how the drug compares with other currently used agents. Nedocromil sodium has been directly compared with all of the antiasthmatic medications currently used in the United States including theophylline, β-adrenergic agents, inhaled corticosteroids, and cromolyn sodium. The results of these studies indicate that for the treatment of mild-to-moderate asthma, nedocromil sodium provides a safe and clinically effective antiinflammatory addition to the physician's armamentarium of antiasthma drugs.

Background: Platelet activation by platelet activating factor (PAF) seems to be involved in the inflammatory process in asthma and may serve as a possible target for the antiinflammatory drug nedocromil sodium, which is known to inhibit cell activation by different stimuli. Methods: We investigated the effect and the mode of action of nedocromil sodium on platelet activation by PAF. In a set of healthy volunteers ( n = 45) we investigated seven different parameters of platelet activation by PAF, thrombin, and Ca 2+ -ionophore. Results: Nedocromil sodium inhibited: (1) PAF-induced "shape change" reaction up to 78% (50% inhibitory concentration [IC 50 ]: 3 × 10 −9 mol/L), thrombin-mediated "shape change" up to 80% (IC 50 : 2 × 10 −8 mol/L), but not the Ca 2+ -ionophore-dependent reaction, (2) platelet aggregation by PAF up to 85% (IC 50 : 2 × 10 −9 mol/L); (3) release of thromboxane B 2 up to 82% (IC 50 : 5 × 10 −9 mol/L); (4) formation of inositol 1,4,5-triphosphate by PAF (IC 50 3 × 10 −7 mol/L), by thrombin (IC 50 : 1 × 10 −9 mol/L), but not by Ca 2+ ionophore; (5) increase of intracellular free calcium (IC 50 : 4 × 10 −7 mol/L); (6) formation of diacylglycerol (IC 50 : 9 × 10 −9 mol/L), and (7) translocation of protein kinase C (IC 50 : 1 × 10 −9 mol/L). Conclusions: In the concentration range of the IC 50 values found in these experiments, nedocromil sodium reduced PAF binding to platelets by only 10% to 20%, such that this interference cannot explain the observed effects of the compound. Inhibition of receptor-mediated platelet activation at an early stage in the signal transduction pathway, and without effect on Ca 2+ -ionophore-—induced platelet activation, suggests an action of nedocromil sodium at the level of the cell membrane.

Tryptase and chymase released from activated mast cells degrade the neuropeptides calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) to peptide fragments. We have examined whether nedocromil sodium can modulate the ability of rat activated peritoneal mast cells to degrade 125I-CGRP and 125I-VIP. Mast cell-dependent degradation of both 125I-CGRP and 125I-VIP was observed with compound 48/80 (0.03-1 microgram/ml) and in the case of 125I-VIP with anti-IgE (1-20 micrograms/ml). Nedocromil sodium (10(-6)-10(-4) M) caused significant inhibition of neuropeptide degradation, with the most effective inhibition observed against anti-IgE-induced degradation of 125I-VIP. Nedocromil sodium had no inhibitory effect on the ability of lysed mast cells, bovine trypsin or chymotrypsin to breakdown 125I-VIP. These results suggest that nedocromil sodium inhibits mast cell-dependent degradation of neuropeptides, such as VIP, as a secondary consequence of inhibiting the release of mast cell proteases.

Background: Nedocromil sodium has proven to be efficacious in prophylactic and long-term therapy for the treatment of seasonal allergic rhinitis. We examined the speed of onset of intranasal nedocromil sodium (1%) for relief of symptoms due to ragweed allergic rhinitis. Methods: In a double-blind, placebo-controlled trial, 104 patients received either nedocromil sodium or placebo four times daily. Patients spent 10 hours per day for 2 consecutive days in Iowa City Park during the peak of ragweed season. Only patients who had significant symptoms during 3 hourly baseline assessments received drug. Symptom scores for stuffy nose, runny nose itchy nose, and sneezing and global symptom summary scores were recorded at 19 hourly time points during the 2 days. In the evening patients recorded symptom scores for the postexposure period. Results: In comparison with placebo, nedocromil significantly improved rhinitis symptoms as evidenced by lower symptom summary scores within 2 hours ( p = 0.016). Further, this reduction in rhinitis symptoms was maintained throughout the 2-day pollen exposure period. After patients left the study site, postexposure symptom summary scores were also significantly lower in patients treated with nedocromil compared with those treated with placebo ( p Conclusions: Nedocromil significantly relieved preexisting seasonal allergic rhinitis symptoms during peak pollen exposures within 2 hours of the first doss and the therapetuic benefits were maintained on a dosing regimen of four times a day.

Nedocromil sodium, a topical antiinflammatory agent recommended as a prophylactic regimen for asthma, is known to inhibit both allergic and nonallergic inflammatory processes in which an essential role for T cells has been implicated. Therefore the direct effects of this drug on several aspects of T-cell activity were analyzed in the present study. By using murine lymphocytes we found that NS at concentrations of 10(-8) to 10(-6) mol/L inhibited the mitogen- or antigen-induced proliferative responses of these cells. It is interesting to note that higher concentrations were ineffective. Preincubation of immune lymph node cells from contact sensitized mice with the drug abrogated their ability to transfer contact sensitivity to naive recipients, an effect that was found to be specific for the treated cells. Nedocromil sodium also interfered with the mitogen-induced interleukin-2 and tumor necrosis factor production by T cells and with their ability to adhere to the bound protein components of the extracellular matrix laminin and fibronectin. All these effects may be attributed to the inhibition of the increase of cytosolic calcium, which accompanies the early phase of T-cell activation and which is an essential step in inducing the aforementioned phenomena.