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.     

Protection of nedocromil sodium on bronchoconstriction induced by inhaled neurokinin A (NKA) in asthmatic patients

Neurokinin A (NKA) has been shown to exert a potent contractile action on bronchial smooth muscles both in vitro and in vivo. Although this effect seems to be due either to a direct action of this peptide on specific muscular receptors or to an indirect effect on mast cells and/or nerves, its mechanism of action in bronchial asthma is still unknown. In the present study we have investigated the airway response to inhaled NKA in 10 asthmatic subjects and the activity of the novel pyranoquinoline dicarboxylic acid drug, nedocromil sodium, on this response. Ten asthmatic patients with stable asthma took part in the study consisting of four separate visits. On the first two occasions we derived histamine and NKA PD15 values in absence of any drug treatment. On the following two visits the inhalation challenge with NKA was performed after administration of either nedocromil sodium or matched placebo administered as pressurized aerosols via metered dose inhalers in a randomized double-blind order. Inhaled NKA produced a dose-related fall in FEV1 in all the subjects studied. Inhaled nedocromil sodium had a significant effect on the FEV1 response to NKA inhalation, the geometric mean PD15 value increasing from 16.6 to 32.2 x 10(-9) mol. We conclude that nedocromil sodium attenuates subsequent responsiveness to inhaled NKA in asthmatic subjects.     

The long-term effect of nedocromil sodium on the maximal degree of airway narrowing to methacholine in atopic asthmatic subjects

Airway hyperresponsiveness in asthma is characterized by increased airway sensitivity and by excessive maximal airway narrowing. Long-term inhalation therapy with nedocromil sodium has been shown to reduce increased airway sensitivity in asthma. However, it is unknown whether it also attenuates excessive airway narrowing. We studied the long-term effects of nedocromil on the maximal degree of airway narrowing to methacholine. Twenty-seven atopic asthmatic adults (21-39 years), with a measurable maximal-response plateau on the dose-response curve (20-55% fall in FEV1), were randomly allocated into two parallel treatment groups. They received either inhaled nedocromil 4 mg q.i.d. or placebo, for 8 weeks following a 2 week baseline period. Every 2 weeks, complete dose-response curves to inhaled methacholine were obtained. The response was measured by FEV1 and by volume history standardized partial expiratory flow-volume curves (V40p). A maximal-response plateau was considered if three or more of the highest data points fell within a 5% response range, the maximal response being the average value on the plateau (MFEV1, MV40p). Airway sensitivity was defined as the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20FEV1) or 40% fall in V40p (PC40 V40p). Twenty-four subjects completed the study. Baseline FEV1 or V40p did not change during either treatment (P greater than 0.07). There were no significant changes in MFEV1 or MV40p during treatment with nedocromil (P greater than 0.07). Neither were these changes significantly different between the two groups (P greater than 0.25).(ABSTRACT TRUNCATED AT 250 WORDS)     

The preventive effect and duration of action of nedocromil sodium and cromolyn sodium on exercise-induced asthma (EIA) in adults

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.     

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.     

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.     

Arachidonate 5-lipoxygenase metabolism in human neutrophils from patients with asthma: in vitro effect of nedocromil sodium.

Among the cells which participate in amplification of the local inflammatory reaction in asthma, neutrophils (PMN) are pro-inflammatory cells that can generate inflammatory mediators and arachidonic acid derivatives in particular. In asthmatic patients (AP) with attacks, the capacity of blood PMN to produce 5-lipoxygenase metabolites was investigated and compared to the response in healthy subjects (HS). PMN from 6 AP and from 6 HS were stimulated by calcium ionophore A23187 and arachidonate 5-lipoxygenase metabolites were analyzed by reverse-phase HPLC. LTB4, 6-trans LTB4, omega OH-LTB4 and 5-HETE were identified. In AP, total LTB4 synthesis was enhanced as compared to synthesis with PMN in HS. But the total 5-HETE synthesis by PMN from AP was decreased. Thus, the inflammatory potential of PMN from AP was enhanced in comparison to HS. The anti-inflammatory effect of nedocromil sodium (NS) was studied in the 5-lipoxygenase metabolism of arachidonic acid. NS (10(-4) mol/l) inhibited total LTB4 synthesized by PMN in AP but not in HS. We conclude that NS affects leukotriene synthesis only in cells with enhanced inflammatory potential.     

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.     

A trial comparing nedocromil sodium (Tilade®) and placebo in the management of bronchial asthma

Abstract. In a double-blind group comparative trial nedocromil sodium (Tilade®) at a dose of 4 mg four times daily was compared with placebo in the management of out-patients with bronchial asthma. Treatments were delivered by pressurized aerosol over a period of 28 days following a 2-week base-line during which patients continued on their usual therapy. Twenty-one patients entered the nedocromil sodium group and twenty entered the placebo group. All were using beclomethasone dipropionate aerosol as maintenance steroid therapy plus intermittent use of a bronchodilator taken by inhalation. The dose of steroid was reduced for all patients after 2 weeks of treatment and again for approximately half the patients after 3 weeks trial treatment. Patients in the nedocromil sodium treatment group improved in respect of Diary Card symptom scores and peak expiratory flow rate (PEFR), and in their requirements for inhaled bronchodilators. Patients in the placebo group were worse, particularly in respect of daytime asthma symptoms ( P < 0·01), bronchodilator use ( P < 0·05) and morning PEFR during the third week of trial treatment ( P < 0·05). More patients in the nedocromil sodium group than in the placebo group thought their treatment had been effective ( P < 0·05). Nedocromil was well tolerated. Despite the short duration of treatment imposed at this stage in the clinical evaluation of a new compound, our results were sufficiently encouraging to prompt further evaluation of nedocromil sodium over the longer period required (3–12 months) for the clinical assessment of a new treatment for chronic asthma.     

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.     

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.     

The effect of intranasal nedocromil sodium on viral upper respiratory tract infections in human volunteers

Two studies involving double-blind group comparative trials in human volunteers compared the effects of intranasal nedocromil sodium (2.6 mg active drug per nostril, q.i.d.) with placebo on clinical symptoms and performance impairment associated with the common cold. In the first study volunteers were challenged with rhinoviruses (RV9 and RV14), and in the second study with respiratory coronavirus. In both studies, active and placebo groups of volunteers were demographically similar. Infection rates in both groups were also similar. There were no withdrawals resulting from unusual symptoms related to either treatment. In the rhinovirus study (19, placebo; 20, nedocromil sodium) daily symptom scores and daily mean nasal secretion weights were significantly lower in the nedocromil sodium-treated group. In the coronavirus study (26, placebo; 27, nedocromil sodium) there was little difference in the severity of colds between the active and placebo-treated groups, but trends favoured nedocromil sodium. In both studies the impairment of performance in volunteers who developed a cold was significantly less in those treated with nedocromil sodium than in those treated with placebo.     

The effect of nedocromil sodium on the early and late reaction and allergen-induced bronchial hyperresponsiveness.

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.     

A double-blind, placebo-controlled study to assess the efficacy of nedocromil sodium in the management of childhood grass-pollen asthma

The aim of this double-blind placebo-controlled trial was to assess the efficacy and tolerance of nedocromil sodium at a dose of 4 mg four times daily, in the management of children suffering from grass-pollen asthma. Thirty-one children suffering from seasonal asthma (24 boys and seven girls, aged 4-21 yr, mean 11 yr) were enrolled in the study during the 1988 pollen season. Only one child was aged 4 yr, and she was a cooperative girl able to use the metered dose inhaler properly. In addition, in each group there was a patient aged 20 and 21 years, respectively, who had been followed up by us since childhood. Treatments were delivered by pressurized aerosol over a period of 4 weeks following a 1-week baseline, during which patients were required to show active disease by obtaining a minimum symptom score (almost 2 points of severity score on at least 3 days of the baseline period). The patients were randomly assigned to both treatment groups, all were taking inhaled or oral bronchodilators, when necessary. Twenty-nine patients completed the trial, 16 in the nedocromil sodium treatment group and 13 in the placebo group. One child of each group was withdrawn due to treatment failure. Statistically significant differences in favour of nedocromil sodium were found regarding morning tightness and mean morning PEFR values on diary cards (P less than 0.01 and P less than 0.05, respectively), bronchodilator usage (P less than 0.05), pulmonary function tests (PFT) at clinic visits (P less than 0.05), and in parents' opinion (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of adding nedocromil sodium (Tilade®) to the routine therapy of patients with bronchial asthma

In a 12-week double-blind, group comparative trial, preceded by a 2-week baseline period, 38 asthmatic subjects of mixed aetiology and varying severity received either 4 mg nedocromil sodium by metered dose inhaler twice a day or a matching placebo preparation, in addition to their existing maintenance therapy of inhaled corticosteroids plus inhaled bronchodilators. Asthma severity and lung function were assessed at 4-weekly clinic visits, and symptomatology (morning tightness, daytime asthma, cough, night-time asthma), morning, afternoon and evening PEFR, and the use of inhaled bronchodilators were recorded on daily diary cards. Treatment with nedocromil sodium led to significant (P less than 0.05) improvements in clinic assessment of FEV1 and PEFR both before and after an inhaled bronchodilator from at least the eighth week onwards. Mid-study FVC was also significantly (P less than 0.05) improved. Daily PEFR increased throughout the study in the nedocromil sodium-treated subjects and the diurnal variation was reduced. Daily symptom severity was also reduced and these improvements occurred despite the similar or slightly reduced use of inhaled bronchodilators. However, none of these improvements in diary card parameters reached statistical significance. By the final week of the study subjects treated with nedocromil sodium predominantly had a mild form of asthma or no symptoms at all, and both patients and clinicians reported the effectiveness of nedocromil sodium; the subjects but not the clinicians finding it significantly more effective (P less than 0.05) than placebo. Nedocromil sodium was well tolerated although one patient was withdrawn owing to a persistent sore throat after 7 weeks of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the effects of nedocromil sodium and beclomethasone dipropionate on pulmonary function, symptoms, and bronchial responsiveness in patients with asthma

The efficacy of nedocromil sodium (NED) (4 mg twice daily) and beclomethasone dipropionate (BDP) (200 micrograms twice daily) in controlling the symptoms of asthma, the pulmonary function, and bronchial responsiveness to histamine was assessed in a double-blind, double-dummy, crossover study of 39 adult patients with chronic asthma. The patients, most of whom were assessed to be affected to a moderate degree, were insufficiently controlled in their current regimen of inhaled and/or oral bronchodilators. A 2-week baseline period preceded 6 weeks of treatment with each of the study drugs. Both treatment groups demonstrated improvements from baseline in clinical assessment of lung function performed after the first 6 weeks of treatment. No significant differences were observed when the effects of the treatments were compared on FEV1, FVC, and peak expiratory flow. Bronchial reactivity to histamine, measured as the amount of histamine causing a 20% fall in FEV1 (PC20), decreased significantly (p less than 0.05) after 6 weeks of treatment with BDP compared to the effect of NED treatment. Asthma severity, symptom score, and inhaled bronchodilator use demonstrated significantly better results with BDP. After crossover of treatment, the group transferring from NED to BDP continued to improve, whereas the group crossing from BDP to NED tended to demonstrate a major deterioration during the first 3 weeks, after which a stabilization or an increase in FEV1, FVC, and ln PC20 appeared to occur. It is concluded that NED for inhalation is a potent new drug for treatment of both atopic and nonatopic subjects with asthma. With the number of patients and dosages used, the effect on the pulmonary function was not significantly different from that of BDP after the initial 6 weeks of treatment, but BDP had a better effect on asthma severity, overall opinions, symptom score, bronchodilator use, ln PC20, and morning peak expiratory flow.     

Effect of nedocromil on antigen-induced bronchoconstriction in asthmatic subjects

Nedocromil sodium, a pyranoquinoline decarboxylic acid derivative, is a new antiasthma compound undergoing clinical investigation. It has been shown to be effective in the management of asthma and to attenuate exercise-induced bronchoconstriction. We performed a randomized, double-blind, placebo-controlled, crossover study in 12 ragweed-sensitive subjects known to respond to inhaled ragweed antigen. On two study days, four to ten days apart, ragweed challenges were performed using a standard protocol 30 minutes after a single dose (two puffs of 2 mg/puff) of either active drug or placebo. The PD20 (20% fall in FEV1) for each treatment day was compared by parametric and nonparametric 2-period crossover analyses. Baseline FEV1 pre-drug and post-drug administration did not differ significantly between study days. On the nedocromil day, the mean +/- SD for log PD20 was 2.25 +/- 0.561 and on the placebo day, 1.73 +/- 1.048 (P = 0.04). There were no side effects associated with either treatment. These results demonstrate that nedocromil is effective in shifting the stimulus response curve to inhaled antigen in some ragweed-sensitive subjects. Its wide spectrum of efficacy against bronchoprovocation suggests it is useful in the treatment of hyperreactive airway disorders.     

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.