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Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used clinically to prevent allergic reactions to common allergens. Despite the relative success of the most commonly prescribed mast cell stabilizer, disodium cromoglycate, in use for the preventative treatment of bronchial asthma, allergic conjunctivitis and vernal keratoconjunctivitis, there still remains an urgent need to design new substances that are less expensive and require less frequent dosing schedules. In this regard, recent developments towards the discovery of the next generation of mast cell stabilizing drugs has included studies on substances isolated from natural sources, biological, newly synthesized compounds and drugs licensed for other indications. The diversity of natural products evaluated range from simple phenols, alkaloids, terpenes to simple amino acids. While in some cases their precise mode of action remains unknown it has nevertheless sparked interest in the development of synthetic derivatives with improved pharmacological properties. Within the purely synthetic class of inhibitors, particular attention has been devoted to the inhibition of important signalling molecules including spleen TK and J AK3. The statin class of cholesterol-lowering drugs as well as nilotinib, a TK inhibitor, are just some examples of clinically used drugs that have been evaluated for their anti-allergic properties. Here, we examine each approach under investigation, summarize the test data generated and offer suggestions for further preclinical evaluation before their therapeutic potential can be realized. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 [ABSTRACT FROM AUTHOR]

There are few controlled studies on the effects of anti-inflammatory treatment on airway inflammation in newly diagnosed childhood asthma. Sixty children with newly diagnosed mild persistent asthma, 5–10 years of age, and 17 healthy control subjects were studied. Asthmatic children were randomized into an open study with two treatment groups: (1) budesonide 400 μg twice daily for 1 month, 200 μg twice daily for 5 months and (2) disodium cromoglycate (DSCG) 10 mg three-times daily for 6 months. All exacerbations were treated with budesonide 400 μg twice daily for 2 weeks. Symptoms and lung function were recorded throughout the study. Sputum induction was safe and the overall success rate was 71%. This improved with age and decreased after treatment. At baseline, the asthmatic children had more eosinophils in blood (0.26 vs 0.18 × 109/l, P = 0.03) and sputum (1.1 vs 0.0 %, P = 0.0001) than the control subjects. The numbers of sputum eosinophils correlated with bronchial responsiveness ( R = −0.58, P = 0.0002). Eosinophils were higher in children with atopic asthma than with nonatopic asthma ( P < 0.0001), and in children with a history wheezing than in children without wheezing ( P = 0.02). Six months of budesonide treatment, but not of DSCG, improved lung function ( P = 0.007), decreased symptoms ( P = 0.007) and sputum eosinophils ( P = 0.003). The effects of budesonide were pronounced in children with intense sputum eosinophilia (>3%). Sputum eosinophilia is present in children with newly diagnosed mild persistent asthma. Treatment with inhaled budesonide, but not with DSCG, decreases sputum eosinophils along with clinical and functional improvement. [ABSTRACT FROM AUTHOR]

1 We have explored the effects of bacterial endotoxin (lipopolysaccharide: LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5-hydroxytryptamine. 2 In vehicle-challenged animals, adenosine. given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS 0.3 mg kg[sup-1] bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier lime point and there were substantial increases in each marker of inflammation in BAL fluid. 3 The bronchoconstrictor response to adenosine was blocked selectively by methysergide. disodium cromoglycate and the broad-spectrum adenosine receptor antagonist. 8-SPT, but not by DPCPX or ZM 243185. selective antagonists for the A[sub1]and A[sub2A]receptors, respectively. 4 Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8-SPT but not by selective A[sub1]or A[sub2A]receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine. [ABSTRACT FROM AUTHOR]

Background Eosinophil cationic protein (ECP) is one of the major, cytotoxic molecules produced by eosinophils, which can be used as a marker of allergic inflammation. Objective In this placebo-controlled study we measured nasal and serum ECP levels to verify their possible role in monitoring the efficacy of anti-inflammatory therapy in allergic chronic rhinitis in 38 children aged from 4 to 14 yr. allergic to house dust mites. Method Nasal ECP. by the method of direct incubation on nasal mucosa, and serum ECP were determined before and after 3 weeks of treatment with flunisolide nasal spray 50 µg twice/daily (13 cases, Group I), disodium cromoglycate (DSCG) 10.4 mg three times/day (15 cases, Group 2) and placebo (10 cases, Group 3). The effectiveness of therapy was evaluated clinically and correlated to serum and nasal ECP values. Results Before treatment no significant difference emerged in the clinical scores of the three groups of patients. Before and after treatment serum FCP levels were not statistically different from normal controls. Before treatment nasal ECP was significantly higher in all patients compared with controls (P < 0.001). Nasal ECP decreased significantly in flunisolide-treated patients (P < 0.01) (before therapy: median 111 µg/L, range front 33.6 to 200 µg/L; after therapy: median 36.8 µg/L, range from 2.6 to 196 µg/L), but not in DSCG-treated patients, (before therapy: median 66.2 µg/L, range from 32.3 to 200 µg/L; after therapy: median 60.4 µg/L, range from 7.9 to 144 µg/L). No significant variation was present in the placebo group. Clinical improvement was statistically significant after flunisolide therapy (P < 0.05), less evident after DSCG (P = 0.06). Conclusion Serum ECP in chronic allergic rhinitis has been shown to be not useful in monitoring allergic inflammation, but nasal ECP, determined by mucosal incubation, may be used to evaluate the activity of eosinophils and monitor the anti-inflammatory efficacy of therapy in chronic rhinitis. [ABSTRACT FROM AUTHOR]

In some cases that have been diagnosed as contact allergy to nickel, there are repeated cutaneous eruptions of pompholyx, even in areas with no direct contact with the metal. The possible alimentary origin of dyshidrotic eczema should be considered when deciding on therapy. We have collected the clinical data for 24 patients with dyshidrotic eczema caused by nickel, to evaluate the benefit of a low-nickel diet versus treatment with oral disodium cromoglycate, comparing both objective and subjective symptoms. A low nickel diet does not improve these patients but those treated with DSCG reacted better, from both objective and subjective point of view, than either the controls or the patients treated by diet. We next did intestinal permeability tests before therapy and after 15 days of treatment. We found that nickel uptake diminishes simultaneously with the reduction of absorption through the smaller aqueous "pores". This phenomenon was greatest after DSCG. We suggest that DSCG can help selected cases of pompholyx. [ABSTRACT FROM AUTHOR]

The nasal mucociliary clearance is an important defense mechanism of the upper respiratory tract. It is known to be influenced by many pharmacologic substances. We investigated the effects of three topical intranasal antiallergic formulations containing disodium cromoglycate (DNCG), dimethindene maleate (DMM), and azelastine-HCL (AZL) on nasal ciliary beat frequency (CBF) in vitro. Nasal ciliated cells were harvested from 16 healthy volunteers. Cells were diluted 1:10 in culture medium and incubated with a placebo formulation (PLAC), containing 0,022% benzalkonium chloride, which was part of all formulations, a registered 2% formulation of DNCG, a 0.1 % formulation of DMM, and a registered 0.1 % formulation of AZL. After an incubation period of 20 min, CBF was registered by a photoelectric measurement device. Under control conditions (CONTROL), CBF was 11.4±1.3 Hz. PLAC reduced CBF to 9.7±2.3 Hz (NS). DNCG reduced CBF to 9.7±2 Hz (NS). DMM reduced CBF to 7.2±1.7 Hz (P≤0.05 vs CONTROL, NS vs PLAC), and AZL reduced CBF to 0.9±1.8 Hz (P0.001 vs CONTROL, P≤0.001 vs DNCG, P≤0.001 vs PLAC). In conclusion, a possible influence of antiallergic intranasal formulations on nasal ciliary function has to be considered in clinical application. [ABSTRACT FROM AUTHOR]

Fluticasone propionate aqueous spray, a new intranasal corticosteroid preparation, and disodium cromoglycate 2% aqueous nasal spray, an established preventive treatment for seasonal allergic rhinitis, were compared in a double-blind, double-dummy, parallel-group, multicentric study m France A total of 218 patients with seasonal allergic rhmitis caused by grass pollen (verified by positive skin prick test) were preventively treated before the onset of the grass pollen season with either fluticasone propionate 200 μg once daily or disodium cromoglycate 5.2 mg four times daily. Half of these doses was given in each nostril. Treatment started before the onset of the pollen season in most patients (178/218). Diary cards, including symptoms of rhinitis and usage of nasal sprays, were filled m twice daily for 6 weeks. Terfenadine in 60-mg tablets and eye-drops could be used as rescue medications We treated 110 patients with fluticasone propionate and 108 patients with disodium cromoglycate. Patients treated with fluticasone propionate had significantly more days free of primary eflicacy symptoms of sneezing (P < 0.001) and nasal discharge during the day (P = 0.002), as well as free of all the other nasal symptoms (P <0.01), and significantly lower median scores (P < 0.05) for all nasal symptoms except nasal discharge than patients treated with disodium cromoglycate. There was no difference in eye symptoms or in rescue medication use between the two groups. Compliance with the treatment was assessed. Eleven patients recorded incorrect use of both nasal sprays for over 25% of days, and 55 patients recorded incorrect use of four-times-daily spray only; no patient recorded incorrect use of morning spray only. Both treatments were generally well tolerated. [ABSTRACT FROM AUTHOR]

In order to compare long-term changes induced on a wide spectrum of bronchial hyperre-activity (BH) by the antiallergic drugs disodium cromyglycate (DSCG) and ketotifen, 56 asthmatic patients (age range 15-55 years) were studied. Patients were allocated to three groups with similar age and BH level. During 2 months, 15 individuals inhaled 20 mg DSCG four times a day. 14 took ketotifen 1 mg twice a clay orally and 14 one placebo (lactose) capsule twice a day. After preliminary results, an additional group of 15 patients took clemastine 1 mg orally twice a day for 1 week. Only the ketotifen and clemastine groups differed significantly from the placebo group on shifting log dose-response curves of inhaled histamine, in addition, no significant difference was seen between the ketotifen and clemastine groups. These results suggest that changes induced by ketotifen were mainly related to its powerful antihistamine action; similarly, nonspecific BH is not wholly dependent on mediator release. [ABSTRACT FROM AUTHOR]

Fourteen adults and 10 children with active atopic dermatitis entered this double blind cross-over study of oral disodium cromoglycate (DSCG) (adults 200 mg qid, children 100 mg qid) compared with placebo. Oral DSCG and placebo were given for 6 weeks in random order. According to the investigators' assessments of eczema, significant differences between active and placebo were found after 6 weeks' treatment, DSCG being favoured (p < 0.05). No differences were detected in the investigators' assessment of lichenization and overall disease. No significant differences between the two treatments were demonstrated in the patients' assessments. Results from food allergic patients. Two patients reported possible side effects of arthralgia and urticaria respectively. There were no treatment effects on serum IgE values or any other laboratory data. [ABSTRACT FROM AUTHOR]

Fourteen boys with a mean age of 1.2.2 years were studied with respect to the protective effect of ketotifen on exercise-induced asthma (EIA) in comparison with disodium cromoglycate (DSCG). All had a positive history of EIA and a post-exercise fall in FEV1 of more than 20%. A double blind cross-over technique was used with a 1 week wash-out period between the two treatment alternatives. Both drugs gave some, but not significant protection for EIA and no differences between the two active substances tested were found. Great individual differences in the response to the two drugs were noted. [ABSTRACT FROM AUTHOR]

Thirty-six children with a mean age of 8.9 years were studied with respect to the prophylactic effect and tolerance of ketotifen in comparison with disodium cromoglycate. All had a verified deciduous tree pollen-induced asthma. The children were stratified into two matched groups and the double-blind technique was used. The study was performed during the whole deciduous tree pollen season. Daily pollen counts were performed during the whole observation period as well as daily registrations of allergic symptoms, additional medication and pulmonary expiratory flow. No significant differences were found between the two substances tested. No adverse reactions or side effects were noted. [ABSTRACT FROM AUTHOR]

The in vitro effect of disodium crotnogiycate (DSCG) on IgE antigen-induced mast cell degranulation is described- Serum from an egg white allergic patient was used to sensitize jejunal mucosa from nine individuals. Egg white was used to challenge the IgE seiisitized mast cells. DSCG in concentrations 3 × 10-7 M to 3 × 10-4 M was added to the mucosal specimens before antigen challenge. Mast cell degranulation in the sensitized specimens challenged with egg white was 88%. Mast cell degranulation in sensitized specimens created with DSCG before and during antigen challenge was reduced to 2% at a concentration of 8 × 10-5 M of DSCG (P = 0.006) and to 28% at a concentration of 3 × 10-7 M (P = 0.027). No significant reduction of mast cell degranulation was seen at concentrations of 3 × 10-7 M and 3 × 10-4 M. [ABSTRACT FROM AUTHOR]

In a food allergic patient challenge evoked a dual asthmatic response. These reactions could be partly or completely blocked by pretreatment with disodium cromoglycate (Intal, Lomudal) orally, depending on the doses given. Pretreatment with inhalations of disodium cromoglycate gave no protection. [ABSTRACT FROM AUTHOR]

Oral disodiumcromoglycate (DSCG) has been used for many years in the prevention of food allergic reactions. The reported effectiveness varies widely and little is known about the mode of action. The aim of this study was to evaluate the effect of DSCG pretreatment (2 x 100 mg) on intestinal permeability (IP), as measured with a sugar absorption test (SAT), in relation to the clinical response during food challenge in 30 children suspected of cow's milk allergy. In the SAT the urinary Lactulose/Mannitol (L/M) ratio was measured after oral administration of these compounds. DSCG pretreatment did not alter the number of clinically positive challenges. Children with clinically positive challenges showed a significant increase in the L/M ratio with placebo pretreatment as compared to children with clinically negative challenges (p = 0.0008). This difference was reduced to nonsignificant levels after DSCG pre-treatment (p = 0.07). We conclude that DSCG in this dosage probably reduces the local intestinal response but does not prevent the extra-intestinal reactions. [ABSTRACT FROM AUTHOR]

We report a case of hyperimmunoglobulin E syndrome (HIE) complicated by neutrophil deficiency which was successfully treated with oral administration of disodium cromoglycate. A 48-year-old Japanese man with HIE developed Streptococcus pneumoniae meningitis. Laboratory tests after the meningitis revealed persistent neutropenia (300-800/mm³) and defects of phagocytosis and bacterial killing by neutrophils. Administration of disodium cromoglycate was started, and neutrophil counts gradually increased to 1200-1600/mm³. The impaired neutrophil activities returned to normal. The patient improved clinically; during the 2-year treatment, he had only two brief episodes of the common cold. Disodium cromoglycate may have potential clinical use in the treatment of cases of HIE even with neutrophil deficiency. [ABSTRACT FROM AUTHOR]