Search

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.

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.

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.

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.

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.

Nedocromil sodium (NS) has been shown to inhibit the late asthma response to inhaled antigen and to control symptoms in chronic asthma; in both processes the eosinophil is thought to be an important contributor. To understand the antiinflammatory actions of NS in asthma, its effects on three eosinophil functions were evaluated: (1) change in cell density during in vitro culture, (2) synthesis of leukotriene C 4 (LTC 4 ), and (3) generation of superoxide anion. In these studies normal density (>1.095 gm/ml) purified human peripheral blood eosinophils were cultured for 24 hours in 50% conditioned medium from cow pulmonary arterial endothelial cells. After incubation, 45.2% ± 8.0% of the eosinophils had a density less than 1.085 gm/ml. In the presence of NS (10 μmol/L), only 32.0% ± 7.5% became less dense ( p = 0.0393). In contrast, NS had no effect on changes in cell density after a 20-minute exposure of eosinophils to functional activators N -formyl-methionyl-leucyl-phenylalanine (0.1 μmol/L) or platelet activating factor (0.1 μmol/L). Furthermore, calcium ionophore-activated LTC 4 secretion was found to be significantly inhibited by NS (3.8 ± 0.6 ng/ml vs 2.4 ± 0.3 ng/ml with 1 μmol/L NS or 1.7 ± 0.6 ng/ml with 10 μmol/L NS, p

Bronchial hyperresponsiveness (BHR) to methacholine was studied in 14 patients with asthma and five healthy control subjects, with and without pretreatment with nedocromil sodium, 3 and 24 hours after allergen challenge. Eleven patients demonstrated a dual asthmatic response. A significant decrease in the provocative concentration causing a 20% fall in FEV1 was found from a geometric mean starting value of 1.18 mg/ml on the control day to 0.24 mg/ml (p less than 0.001) and to 0.17 mg/ml (p less than 0.001) 3 and 24 hours after allergen challenge. A significant correlation was observed between the increased BHR at 3 hours and the magnitude of the late response (r = -0.57; p less than 0.05). Nedocromil sodium (6 mg) significantly inhibited the increase in BHR, 1 mg/ml (p less than 0.001) at 3 hours and 0.50 mg/ml (p less than 0.001) at 24 hours. Nedocromil sodium shifted the severity of the early allergic reaction (EAR) from mean -34.8% to -6.9% and inhibited the later allergic reaction (LAR) from -30.5% to +0.4% (p less than 0.005). From the study can be concluded that nedocromil sodium inhibits the EAR and LAR and the allergen-induced increase in BHR. The inhibitory effect of nedocromil sodium on the LAR may be related to its ability to inhibit the increased BHR before the development of the LAR.

We have obtained biopsy specimens of the nasal mucous membrane before and during the grass-pollen season in 22 patients with seasonal allergic rhinitis to grass pollen to assess the effects on cellular infiltration of natural exposure to allergen. Biopsy sections were examined by light microscopy, and quantitative assessment was made of numbers of mast cells and eosinophils. The patients were divided into 11 who were treated with placebo and 11 patients who were treated with topical nedocromil sodium. In the group as a whole, there was a significant (p less than 0.001) increase in mast cell density in tissue sections from biopsy specimens obtained during the season compared with out of season (median values, 55.0 and 15.5 cells per square millimeter, respectively). There was also a significant (p less than 0.02) increase in the density of eosinophil infiltration during the season compared with out of season (median values, 6.3 and 0 cells per square millimeter, respectively). Treatment with nedocromil sodium significantly (p less than 0.02) inhibited the accumulation of mast cells but not eosinophils. Compared with the placebo-treated group, the group treated with nedocromil demonstrated a significant (p less than 0.025) reduction in the requirements for treatment with concomitant medication (terfenadine tablets and xylometazoline/antazoline eye drops). These results indicate that natural exposure to allergen in patients with seasonal allergic rhinitis is accompanied by infiltration of mast cells and eosinophils into the nasal mucous membrane. The clinical efficacy of nedocromil sodium in this condition may be related to inhibition of infiltration by mast cells.

The generation of platelet-activating factor (PAF) and leukotriene C 4 (LTC 4 ) from normodense human eosinophils (EOSs), stimulated with unopsonized zymosan or calcium ionophore A23187, has been studied. There was a zymosan time- and dose-dependent increase in both PAF and LTC 4 production. A plateau of 0.11 ± 0.04 ng of PAF per 10 6 EOSs (mean ± SEM; n=7) and of 1.38 ± 0.58 ng of LTC 4 per 10 6 EOSs (n = 5) was reached at 5 × 10 8 zymosan particles at 37 ° C for 30 minutes. Under optimal conditions, 91 ± 1% of the PAF and 66 ± 13% of the LTC 4 remained cell associated. Calcium ionophore A23187 induced a time- and dose-dependent increase in the quantities of PAF and of LTC 4 generated by EOSs. A plateau of 31 ± 13 ng of LTC 4 per 10 6 EOSs (n = 5) was reached at 1 μmol/L of calcium ionophore A23187 at 37 °C for 15 minutes. The dose response for PAF generation reached 4.2 ± 0.8 ngl10 6 EOSs (n = 8) at 10 μmol/L of calcium ionophore A23187 at 37 °C for 15 minutes and had not plateaued; 90 ± 5% of the generated PAF was cell associated. In vitro preincubation of EOSs with 10 −8 to 10 −4 mol/L of nedocromil sodium for 15 minutes did not change the subsequent generation or cellular distribution of PAF or LTC 4 in EOSs optimally stimulated with either zymosan or calcium ionophore A23187.

It is known that cromolym sodium and nedocromil sodium share similar antiallergic properties. This study examined whether nedocromil sodium, a pyranoquinoline dicarboxylic acid, could inhibit sulfur dioxide (SO2) bronchoconstriction in a dose-dependent manner in 10 men with mild asthma. Previous studies have shown that cromolyn sodium produces such inhibition in allergic monkeys and asthmatic subjects. Subjects in this double-blind, placebo-controlled study were nonsmoking men between the ages of 23 and 40 years (mean age, 30.7 years). The study took place over 5 days within a 3-week period. On the first of 5 days, each subject had a history taken and physical examination, SO2 baseline test, laboratory testing, and a methacoline dose-response test. On each of 4 test days, the subjects received pretreatment with either placebo or a 2, 4, or 8 mg dose of nedocromil sodium in a randomized, double-blind sequence, followed after 30 minutes by an SO2 dose-response test. Results showed that maximum bronchoconstriction response to SO2 was significantly attenuated (p0.01) by all three doses of nedocromil sodium, with small differences noted between dose levels. We concluded that nedocromil sodium inhibited SO2-induced bronchospasm at dose levels as low as 2 mg.

We have investigated the effects of BN 52021 (a specific PAF antagonist derived from Ginkgo biloba ) on PAF-induced human eosinophil and neutrophil chemotaxis. In response to an optimal concentration of PAF (10 −6 mol/L), the drug was significantly more potent ( p −6 mol/L and 2.3 (±0.2) × 10 −5 mol/L for eosinophils and neutrophils, respectively. Sodium cromoglycate, nedocromil sodium, salbutamol, and dexamethasone (preincubated with cells up to 6 hours) had no effect over a wide dose range (10 −3 to 10 −9 mol/L). BN 52021 was significantly more effective in inhibiting chemotaxis when the cells were preincubated with the compound for up to 1 hour before commencement of the locomotion assay, whereas washing the cells completely abolished this effect. Inhibition by BN 52021 was specific for PAF in that it had no effect on chemotaxis induced by either leukotriene B 4 , N-formyl-methionyl-leucyl-phenylalanine, or a purified human mononuclear cell-derived neutrophil chemotactic factor. BN 52021 also inhibited the specific binding of [ 3 H]-PAF (10 −8 mol/L) to eosinophils and neutrophils in a concentration-dependent fashion with a concentration of drug required to produce 50% inhibition of 1.5 (± 0.3) × 10 −6 mol/L and 9.1 (±2.5) × 10 −7 mol/L, respectively. These results suggest that BN 52021 has potential as an anti-inflammatory agent in conditions associated with PAF-induced accumulation of neutrophils and eosinophils.

Nedocromil sodium, 4 mg, from a metered-dose inhaler, cromolyn sodium, (cr) 20 mg, from a Spinhaler, and placebo (pl) were compared in their efficacy and duration of action in preventing exercise-induced asthma. Twelve patients with asthma performed treadmill exercise tests 20 minutes, 2 hours, and 4 hours after a single dose of drug in a double-blind, crossover trial. Both active drugs were significantly better than pl at 20 minutes. Two hours after drug administration, only cr was significantly different from pl. The direct comparison between nedocromil and cr demonstrated no significant difference on FEV1, and the only significant difference was with forced expiratory flow between 25% and 75% of vital capacity at 2 hours. It is concluded that at these clinically recommended doses, both drugs are equally effective in preventing exercise-induced asthma with cr possibly having a somewhat longer duration of action.