Intranasal nedocromil sodium in the treatment of ragweed-allergic rhinitis

Nedocromil sodium (NS), a new pyranoquinoline dicarboxylic acid derivative, reported to be effective against both mucosal and connective tissue-type mast cells, was studied in ragweed-allergic rhinitis (RAR). Thirty-six patients with RAR were studied in an 8-week, double-blind, placebo-controlled trial. Stratification was based on prick skin test sensitivity and severity of signs and symptoms of previous RAR. NS (1% solution) in a dose of 0.13 ml of nasal spray was administered to each nostril, a minimum twice daily. Concomitant medications were limited to ingested terfenadine, ocular cromolyn, and inhaled medications. Symptoms and medications were noted daily. Active-treatment and placebo-treatment groups were comparable. There were less symptoms of runny nose and itchy eyes in the active-treatment group (p less than 0.05) and also less antihistamine, p less than 0.004. Patients in the active-treatment group were more likely to conclude that symptoms were improved by the nasal spray (p less than 0.01). No side effects were reported. This study indicates that NS is effective and well tolerated in RAR.     

Regulation of IgE-dependent antiparasite functions of rat macrophages and platelets by nedocromil sodium

The IgE-dependent stimulation of mononuclear phagocytes and blood platelets can be measured by antiparasite cytotoxicity, oxygen-mediated chemiluminescence and, in macrophages, lysosomal enzyme activity. Using these parameters, the present study demonstrated an inhibition by nedocromil sodium of the IgE-mediated triggering of the nonmast cell inflammatory populations in the rat. These observations suggest that nedocromil sodium may be of value in the modulation of IgE-dependent cell activation inducing the release of inflammatory mediators.     

Prevention of fog-induced bronchospasm by nedocromil sodium

A single dose double-blind crossover study was performed to compare the efficacy of nedocromil sodium (4 mg) and placebo administered from pressurized aerosols against bronchoconstriction induced by the inhalation of ultrasonically nebulized distilled water (fog) in twelve asthmatic subjects. Neither active nor placebo pre-treatment produced any significant change in baseline FEV₁ and SRaw. Nedocromil sodium significantly attenuated fog-induced falls in FEV₁ ( P < 0.001) and increased specific airways resistance (SRaw, P < 0.01). The results provide further evidence of the potential therapeutic usefulness of nedocromil sodium in the management of chronic obstructive airways disease.     

Effect of nedocromil sodium on exercise-induced bronchoconstriction in children

A double-blind, placebo-controlled, crossover study investigated the efficacy of nedocromil sodium in reducing bronchoconstriction subsequent to exercise challenge in asthmatic children. Twelve children aged 7-14 years (mean 10.8 years) were pretreated with nedocromil sodium aerosol (2 inhalations; 2 mg/inhalation) or matching placebo, 30 min prior to treadmill running. Lung function was measured at regular intervals postexercise and the mean maximum percentage decrease in PEF and FEV1 compared following nedocromil sodium or placebo pretreatment. Nedocromil sodium significantly reduced the fall in PEF (P less than 0.001) and FEV1 (P less than 0.001) and provided significantly greater protection (P less than 0.001) than placebo. No adverse reactions or unusual symptoms were observed.     

Effect of nedocromil sodium and cromoline sodium on atopic basophil function

Nedocromil sodium (NS) is a new drug for the treatment of bronchial asthma. In the present study, we examined the effect of NS on basophil histamine release stimulated by anti-IgE, anti-IgE + IL-3 (interleukin-3) or ryegrass. The effect of cromoline Na (CrS) on histamine release from basophils to the same stimuli was compared. NS did not affect histamine release from basophils following anti-IgE alone or together with IL-3, but augmented the release following ryegrass. CrS did not affect histamine release after the same three stimuli. We concluded that NS and CrS do not affect bronchial asthma through direct inhibition of histamine release from basophils. Their action may be via an indirect effect on histamine-releasing factor.     

Effects of nedocromil sodium on allergen-induced rhinitis in humans.

Sixteen patients with allergic rhinitis were recruited into a double-blind crossover protocol studying the immediate effect of nedocromil sodium (NS) on the pattern of nasal symptoms and secretions after allergen challenge. After pretreatment with placebo or NS, allergen challenge resulted in pruritus, rhinorrhea, nasal congestion, and/or sneezing within 10 minutes in 12 of 16 subjects. Prostaglandin D2 (PGD2), a marker of mast cell degranulation, increased proportionately with symptom scores, remaining above the 95% confidence interval for 120 minutes after both pretreatments. No difference in PGD2 between the NS-treatment and placebo-treatment days was observed. Protein markers extravasated through the vasculature (albumin and IgG) or secreted by mucosal glands (lactoferrin) were assayed. Total protein, albumin, IgG, and lactoferrin all remained greater than 95% confidence interval for 100 minutes after allergen challenge in the placebo-pretreated group and 120 minutes in the NS-pretreated group. Although there appeared to be a trend for lower secretion of PGD2, albumin, and IgG in the NS-treated group, the overall differences did not achieve statistical significance. This protocol revealed that two topical 130 microliter doses of a 1% solution of NS failed to significantly reduce allergen-induced symptoms, PGD2 generation, or secretion of albumin, IgG, or lactoferrin when NS was compared with placebo. The anti-inflammatory and mast cell-stabilizing effects of NS may require more prolonged pretreatment before provocation to be effective.     

Effects of nedocromil sodium, cromolyn sodium, and a placebo in exercise-induced asthma.

The incidence and severity of exercise-induced asthma were determined in nineteen asthmatic patients who performed eight minutes of exercise following four treatments administered in a random order. The treatments were nedocromil sodium, cromolyn sodium, placebo, and no treatment. It was concluded that nedocromil sodium (8 mg) and cromolyn sodium (4 mg) provide equal protection against exercise-induced asthma.     

Effect of nedocromil sodium on adenosine- and methacholine-induced bronchospasm in asthma

The effect of nedocromil sodium on adenosine-induced bronchospasm was investigated in eight asthmatic patients. Nedocromil sodium (4 mg) administered by aerosol 10 min before challenge, effectively inhibited adenosine-induced bronchospasm. In another group of six asthmatic patients, nedocromil sodium administered in the same way did not reduce the bronchial response to methacholine. These results support the view that adenosine-induced bronchospasm may be prevented by a membrane stabilizing drug and is not mediated through cholinergic pathways. The mechanism(s) by which nedocromil sodium inhibits adenosine-induced bronchospasm requires further investigations.     

The effect of nedocromil sodium on nasal provocation with allergen

We have investigated the effect of nedocromil sodium in preventing the symptoms of rhinitis occurring immediately after allergen provocation in 10 patients with allergic rhinitis. The study had a double-blind, placebo-controlled, crossover design. Nedocromil sodium (1% w/v) and placebo were administered intranasally from identical metered-dose inhalers 20 minutes before allergen provocation. Three variables were measured: nasal airway resistance, the production of secretion, and the number of sneezes. Nedocromil sodium was significantly more effective than placebo in preventing nasal obstruction (p less than 0.01), rhinorrhea (p less than 0.01), and sneezing (p less than 0.05), suggesting that this drug may be useful in the treatment of allergic rhinitis.     

A 3-month evaluation of the efficacy of nedocromil sodium in asthma: a randomized, double-blind, placebo-controlled trial of nedocromil sodium conducted by a Canadian multicenter study group

Nedocromil sodium is a pyranoquinoline dicarboxylic acid derivative, formulated in a metered-dose inhaler. Because nedocromil sodium has in vitro and in vivo anti-inflammatory properties, it was evaluated in a group of steroid-dependent patients with asthma to observe how well it might be tolerated and for evidence of any beneficial effects. In a double-blind, group-comparative study, 127 patients received nedocromil sodium and 61 received placebo, administered as two puffs of 2 mg, four times per day, for 12 weeks. Ten patients developed adverse reactions, seven receiving active drug and three patients receiving placebo. Two patients of each group withdrew because of worsening asthma. Despite selecting patients whose asthma was stable, when they were receiving established therapeutic regimens that included steroids and bronchodilators, it was found that diary-card symptom scores, morning and evening peak expiratory flow rate values, and inhaled beta-agonist usage all demonstrated slight but significant benefit with addition of nedocromil sodium. It is concluded that the inhaled, anti-inflammatory agent, nedocromil sodium, may be added to asthma-treatment regimens with the reasonable expectation of further modest symptomatic benefit.     

Anti-inflammatory effects of nedocromil sodium: inhibition of alveolar macrophage function

The IgE-dependent activation of mononuclear phagocytic cells through their capacity to express low affinity IgE receptors (Fc epsilon RII) has been proposed as a mechanism for the development of airways inflammation in allergic asthma. This Fc epsilon RII expression leads to the IgE-dependent production of the potent pro-inflammatory cytokines IL-1 beta and TNF-alpha. Expression by monocytes of Fc epsilon RII is regulated by several cytokines including interleukin-4, gamma- and alpha-interferons, and granulocyte-macrophage and macrophage colony stimulating factors. An anti-inflammatory effect of nedocromil on monocytes has been proposed as a possible mechanism for its anti-asthma activity. We therefore investigated the capacity of nedocromil to modulate mononuclear phagocyte Fc epsilon RII expression and cytokine production. We used an anti-Fc epsilon RII antibody and flow cytometric analysis to assess the capacity of nedocromil to modulate cytokine-induced Fc epsilon RII expression in normals and asthmatics. Monocytes, THP-1 monocyte leukaemia cells, and alveolar macrophages were exposed to varying concentrations of these cytokines for 48 hr at 37 degrees C with or without the additional presence of nedocromil (1-10 microM) and the per cent of monocytes expressing Fc epsilon RII was determined. No changes in Fc epsilon RII expression were observed. Subsequently, we investigated the capacity of nedocromil to affect the capacity of IgE plus anti-IgE complexes, allergen, and LPS (16 hr/37 degrees C) to stimulate IL-1 beta and IL-6 production. No changes were observed when nedocromil was applied concomitant with the stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of multiple doses of nedocromil sodium given after allergen inhalation in asthma

Aim: Twelve subjects with asthma took part in a placebo-controlled crossover study designed to investigate whether nedocromil sodium given after the occurrence of the early phase asthmatic reaction to allergen has an effect on the late-phase response and the associated increase in airway responsiveness.Methods: The treatments were administered four times at 4-hour intervals at a dose of 4 mg, with the first dose given 1 hour after the last allergen challenge. Changes in airway caliber were monitored for 15 hours after allergen exposure by measuring forced expiratory volume in 1 second hourly. Airway responsiveness to methacholine was determined 24 hours before and 24 hours after allergen challenge.Results: Nedocromil sodium failed to reduce significantly the maximum late fall in forced expiratory volume in 1 second as compared with placebo but delayed its occurrence by 1.5 hours (p = 0.05). Nonspecific airway responsiveness to methacholine was similarly increased after allergen challenge when patients received nedocromil sodium and placebo. No unusual events were reported during the study period by any patient. These results indicate that nedocromil sodium is not able to interrupt the ongoing cascade of inflammatory events leading to the late-phase reaction and the associated increase in airway responsiveness.Conclusion: In allergic asthma, nedocromil can be used only as a preventive treatment.     

Effect of nedocromil sodium on the immediate response to antigen challenge in asthmatic patients

In this double-blind placebo controlled crossover study the protective effect of nedocromil sodium against bronchial allergen challenge was evaluated in ten asthmatic patients. Single doses of 0.5, 1.0 and 2.0 mg nedocromil sodium, administered as a pressurized aerosol 3 hr prior to challenge, were each significantly more effective than placebo in inhibiting allergen-induced bronchoconstriction. The 1.0 and 2.0 mg doses of the active drug were significantly more effective than the 0.5 mg dose. No significant difference was demonstrated between the 1.0 and 2.0 mg doses. Duration of protection beyond 3 hr was not tested. The results suggest that nedocromil sodium may be a potentially useful therapeutic agent and is worthy of further evaluation for the treatment of reversible obstructive airways disease.     

Effect of nedocromil sodium on the late asthmatic reaction to bronchial antigen challenge

The effect of inhaled nedocromil sodium (4 mg by pressurized aerosol) on the dual asthmatic reaction to bronchial antigen challenge was studied in eight patients with asthma. The following prechallenge/postchallenge treatment combinations were administered: nedocromil sodium/placebo, nedocromil sodium/nedocromil sodium, placebo/nedocromil sodium, and placebo/placebo. Each patient received three treatment combinations assigned with a balanced incomplete block design. Nedocromil sodium administered before antigen challenge was significantly more effective than placebo in blocking both the early (p less than 0.001) and late (p less than 0.01) fall in FEV1. Postchallenge administration of nedocromil sodium tended to delay the onset of late asthmatic reaction but did not provide significant protection compared to placebo. These results demonstrated that nedocromil sodium prevents both phases of the dual asthmatic reaction to bronchial antigen provocation when it is inhaled before challenge. Further investigation is necessary to elicit a definite answer to whether nedocromil sodium administered after bronchial challenge has an effect on late asthmatic reaction.     

Attenuation of exercise-induced asthma by pretreatment with nedocromil sodium and minocromil

In a group of atopic adult asthmatic patients the effects of two new inhaled anti-asthmatic drugs, nedocromil sodium and minocromil were studied in two independent randomized double-blind trials to assess their efficacy in preventing exercise-induced asthma (EIA). Exercise testing consisted of steady state running on an inclined treadmill. Neither drug administered 30 min before exercise significantly altered baseline FEV₁. Nedocromil sodium (2 and 4 mg) pre-treatment in nine patients and minocromil (4 mg) in eight patients gave significant protection (P < 0.001) compared to placebo as assessed by the reduction in the maximum percentage fall in FEV₁. There was no significant difference in the inhibitory effect of the two doses of nedocromil sodium. These results indicate that both nedocromil sodium and minocromil can attenuate EIA.     

The effect of nedocromil sodium on the bronchoconstrictor effect of neurokinin A in subjects with asthma

We have previously demonstrated that the neuropeptide, neurokinin A (NKA) (substance K), causes bronchoconstriction in subjects with asthma. In a double-blind, crossover study we investigated the effect of nedocromil sodium on NKA-induced bronchoconstriction in subjects with asthma. Twelve patients with mild asthma (mean FEV1 percent predicted +/- SE, 87.3 +/- 3.4) inhaled on 2 separate days either nedocromil sodium, 4 mg, or placebo, as two puffs from a metered-dose aerosol, 30 minutes before challenge with NKA. NKA was inhaled at three concentrations (10(-7), 3.10(-7), and 10(-6) mol/ml). The specific airway conductance (SGaw) and FEV1 were measured before and 5 and 15 minutes after each concentration step. On the placebo-treatment day, NKA caused a concentration-dependent decrease in SGaw and FEV1 (mean log for the provocative concentration of NKA causing a 35% fall in SGaw [10(-7) mol/ml], 0.49; mean log for the provocative concentration of NKA causing a 15% fall in SGaw [10(-7) mol/ml], 0.90). The inhalation of 4 mg of nedocromil sodium reduced the decrease in both SGaw and FEV1. The maximal percentage decrease in SGaw on the nedocromil sodium-treatment day was 27 +/- 5.2 (versus placebo, 53.3 +/- 5.4; p less than 0.05), and the maximal percentage decrease in FEV1 was 5.5 +/- 1.4 (versus placebo, 12.4 +/- 2.3; p less than 0.05). The dose-response curves for NKA after nedocromil sodium treatment were significantly shifted to the right compared to the curve after placebo-treatment. We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in subjects with asthma.     

Arterial hypoxemia in exercising thoroughbreds is not affected by pre-exercise nedocromil sodium inhalation

It has been reported that pulmonary injury (i.e. capillary stress failure) evoked histamine release from airway inflammatory/mast cells contributes to exercise-induced arterial hypoxemia (EIAH) and that pre-exercise inhalation of nedocromil sodium mitigated EIAH in human subjects 'Med. Sci. Sports Exercise 29, (1997) 10-16'. Because exercise-induced pulmonary hemorrhage due to capillary stress failure is routinely observed in racehorses, we examined whether nedocromil inhalation would similarly benefit EIAH and desaturation of hemoglobin in horses. Two sets of experiments, namely, placebo studies followed in 7 days by pre-exercise nedocromil sodium (30 puffs=60 mg) inhalation experiments were carried out on 7 healthy, sound, exercise-trained thoroughbred horses. In both treatments, arterial and mixed-venous blood-gas/pH measurements were made at rest pre- and post-placebo/drug inhalation, as well as during incremental exercise leading to galloping at 14 m/sec on a 3.5% uphill grade-a workload that elicited maximal heart rate and caused pulmonary hemorrhage in all horses in both treatments, thereby indicating capillary stress failure had occurred. In both treatments, significant (P<0.0001) EIAH of a similar magnitude had developed by 30 sec of maximal exertion, and further significant changes in arterial O(2) tension did not occur as exercise duration progressed to 120 sec. Thus, pre-exercise inhalation of nedocromil sodium was ineffective in modifying the development and/or severity of EIAH in the present study. These findings argue against the airway inflammatory mediator(s) release hypothesis for causing arterial hypoxemia in racehorses.