Treatment of ragweed hay fever with intranasally administered disodium cromoglycate*

In a double-blind study the therapeutic effect of a 4% disodium cromoglycate (DSCG) nasal solution was evaluated in thirty-nine patients with acute symptoms of ragweed hay fever. Patients were randomly assigned to the DSCG or placebo group as they presented with allergic rhinitis. Overall, the DSCG was not more effective than placebo in controlling the symptoms of rhinitis or in decreasing the need for concomitant antihistamines or corticosteroids. Among patients with the highest pretreatment serum ragweed-specific IgE (RW IgE) levels, drug-treated patients had some reduction in symptoms as compared to their placebo controls during the peak of the ragweed pollen season. DSCG treatment did not influence the usual seasonal rise in RW IgE. Side effects from both the active and placebo aerosols were frequent but mild. We conclude that DSCG nasal solution used for the treatment of seasonal ragweed allergic rhinitis is relatively ineffective.     

Inhibition of immediate hypersensitivity reactions by disodium cromoglycate. Requirements for activity in two laboratory models

The ability of disodium cromoglycate to inhibit IgE-mediated cutaneous anaphylaxis in the rat in vivo and release of histamine from peritoneal mast cells in vitro has been studied. Only when drug and antigen were presented to the sensitized cells simultaneously was a dose-dependent inhibition demonstrable. After the drug had been given alone, in the absence of antigen, either in vivo or in vitro it had little or no action when given again at antigen challenge. In vivo, this refractory state was reversible. It is suggested that disodium cromoglycate may act by releasing some factor capable of inhibiting the release of mediators from the mast cell.     

Prevention of pollen rhinitis symptoms: comparison of fluticasone propionate aqueous nasal spray and disodium cromoglycate aqueous nasal spray

Fluticasone propionate aqueous spray, a new intranasal corticosteroid preparation, and disodium eromoglyeate 2% aqueous nasal spray, an established preventive treatment for seasonal allergic rhinitis, were compared in a double-blind, double-dummy, parallel-group, multicentric study in France. A total of 218 patients with seasonal allergic rhinitis 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 in twice daily for 5 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 flutieasone propionate had significantly more days free of primary efficacy 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 < 0.0l), 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.     

Disodium cromoglycate in ragweed-allergic rhinitis.

This study was designed to test the effectiveness of disodium cromoglycate when compared to placebo in a double-blind study in patients with ragweed allergic rhinitis. Patients were selected on the basis of a clinical history and a 4+ reaction to the intradermal injection of water-soluble ragweed, 0.02 c.c. of 500 PNU/c.c. Active agent/placebo groups were selected at random and were on the drug for approximately 8 wk, commencing 1 wk prior to the onset of the ragweed pollen season. Patient response was evaluated using patient diary cards, number of antihistamine tablets taken, and patient interviews. In the Toronto study, of 17 patients on the active drug, 15 were graded as improved, compared to only 6 of 21 placebo-treated patients who were improved. However, in the Hamilton study, results were less impressive. Nonetheless, it appears that intranasal insufflation of disodium cromoglycate was more effective in reducing ragweed hay fever symptoms than placebo.     

Selected immunologic properties of tiprinast, a non-steroidal antiallergy agent

Tiprinast [(3,4-dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]- pyrimidine-2-carboxylic acid] is a new antiallergy compound which shares many of the pharmacological actions of disodium cromoglycate (DSCG). Both compounds inhibit passive cutaneous anaphylaxis in the rat, histamine release from rat peritoneal mast cells and nasal constriction due to antigen in the rat. In all cases tiprinast is more potent than DSCG and also longer acting.     

Mode of action of disodium cromoglycate, studies on immediate type hypersensitivity reactions using `double sensitization'' with two antigenetically distinct rat reagins

The mode of action of disodium cromoglycate has been investigated to determine at what stage in immediate type hypersensitivity reactions the compound is effective. In vitro studies using rat subcutaneous connective tissue sensitized with rat reagin revealed that the compound inhibited the allergic release of histamine if present during antigen challenge. The presence of the compound during sensitization had no effect on antigen-induced release of histamine provided the compound was removed prior to antigen challenge. Tissues which had undergone a primary antigen challenge in the presence of disodium cromoglycate did not release histamine when the compound was removed and the tissues rechallenged. These findings indicated that antigen/antibody interaction occurred in the presence of the compound resulting in desensitization to a subsequent antigen challenge. To corroborate the evidence of the in vitro studies in vivo passive cutaneous anaphylactic reactions (PCA) were undertaken using tissue sites sensitized with two reaginic antibodies which permitted a sequence of antigen challenges. Results from these in vivo reactions demonstrated that it was possible to desensitize tissue, without the release of the mediators of anaphylaxis, by an antigen challenge and disodium cromoglycate treatment. In these sites sensitized with two antibodies the immunological reactivity was maintained following a primary antigen challenge and disodium cromoglycate treatment, as a subsequent challenge with the dissimilar antigen produced a good PCA reaction. It would appear that disodium cromoglycate acts either directly or indirectly at a stage following antigen/antibody reaction but prior to the release of the mediators of anaphylaxis.     

Intraepithelial migration of nasal mucosal mast cells in hay fever

Mast cells were studied by light microscopy in mucosal imprints and in biopsies of nasal mucosa of 12 birch pollen allergic individuals before and during the pollen season, using techniques optimized for the demonstration of mucosal mast cells. We also measured the histamine content of nasal mucosa, whole blood and plasma, and counted the numbers of circulating blood basophils. Before the pollen season the nasal mucosa was found to contain many mast cells located in the mucosal connective tissue stroma, and very few cells with basophilic and metachromatic granules were found in mucosal imprints. During the pollen season there was a redistribution of mast cells into the epithelium, many such cells now being recovered in mucosal imprints. The total number of mucosal mast cells counted in tissue sections did not change significantly with the onset of the pollen season, suggesting a redistribution of mucosal mast cells by migration. Judged by morphologic appearance and naphthol-AS-D chloroacetate esterase activity, the intraepithelial mast cells found in tissue sections had rather the properties of tissue mast cells than of blood basophils, and only a few of the basophilic cells of the imprints had a morphology compatible with blood basophils. The histamine content of the mucosa, as well as histamine levels of whole blood and plasma, and circulating blood basophil numbers did not change significantly in relation to the pollen season. These findings suggest that an intraepithelial migration of mucosal mast cells is part of the allergic mucosal response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy, cost-effectiveness, and tolerability of mometasone furoate, levocabastine, and disodium cromoglycate nasal sprays in the treatment of seasonal allergic rhinitis.

BACKGROUND: Current guidelines recommend intranasal glucocorticosteroids as first-line therapy for seasonal allergic rhinitis. OBJECTIVE: To compare the efficacy, cost-effectiveness, and tolerability of the topical glucocorticosteroid mometasone furoate, the topical antihistamine levocabastine hydrochloride, and the cromone disodium cromoglycate in seasonal allergic rhinitis. METHODS: This study was performed during the 2003 grass pollen season as an open, randomized, parallel-group, single-center study of 123 patients assigned to receive mometasone furoate (200 microg once daily), levocabastine hydrochloride (200 microg twice daily), or disodium cromoglycate (5.6 mg 4 times daily). Symptom scores and nasal inspiratory peak flow measurements were recorded in a patient diary. The global efficacy of the study medication was evaluated by patients after treatment. Eosinophil cationic protein concentrations were measured in nasal secretions before and after treatment. Cost-effectiveness was evaluated as medication cost per treatment success. RESULTS: Mometasone furoate therapy was significantly superior to the use of levocabastine or disodium cromoglycate with respect to all nasal symptoms, the global evaluation of efficacy, and eosinophil cationic protein concentration. Furthermore, mometasone furoate therapy was significantly superior to disodium cromoglycate therapy with respect to nasal inspiratory peak flow. Medication cost per treatment success was lowest with mometasone furoate use and highest with levocabastine use. CONCLUSION: This is the first study to compare mometasone furoate nasal spray with nonsteroidal topical treatments for seasonal allergic rhinitis. Mometasone furoate nasal spray was confirmed as a first-choice topical treatment option for seasonal allergic rhinitis.     

Fluticasone propionate aqueous nasal spray reduces inflammatory cells in unchallenged allergic nasal mucosa: effects of single allergen challenge

BACKGROUND: Topical corticosteroid therapy reduces symptoms and nasal mucosal inflammatory cells in patients with allergic rhinitis. Usually patients are advised to start their medication (1 week) before the beginning of the pollen season. The effect of pretreatment with a topical corticosteroid on unchallenged nasal mucosa is not well documented. OBJECTIVES: The purpose of this study was to investigate, in a double-blind, placebo-controlled study, the effect of 6 weeks' pretreatment with 200 microg twice daily fluticasone propionate on nasal symptoms and inflammatory cell numbers after nasal allergen provocation in patients with seasonal allergic rhinitis. METHODS: Nineteen patients with grass pollen-induced allergic rhinitis were treated for a 6-week period out of the grass pollen season. After completing the treatment period, patients were challenged with grass pollen. Nasal mucosal biopsy specimens were taken 5 times in every patient. In nasal mucosa changes in numbers of T cells, B cells, mast cells, eosinophils, macrophages, and Langerhans' cells were investigated. RESULTS: After 4 weeks of treatment but before allergen provocation, significantly fewer epithelial Langerhans' cells, macrophages, mast cells, T cells, and eosinophils were found in the fluticasone propionate group compared with those found in the placebo group. In the lamina propria significantly fewer Langerhans' cells and eosinophils were found in the fluticasone propionate group. Cell influx in nasal mucosa after allergen provocation was significantly inhibited in the fluticasone propionate group compared with that in the placebo group for epithelial Langerhans' cells, mast cells, macrophages, and T cells and for lamina propria eosinophils, mast cells, Langerhans' cells, macrophages, and T cells. CONCLUSIONS: Fluticasone propionate is effective in reducing early- and late-phase nasal symptoms. Topical corticosteroid treatment reduces inflammatory cells in unchallenged nasal mucosa.     

The inflammatory response to anaphylaxis and intravenous antibody or antigen

Summary The inflammatory process, as initiated by active or passive anaphylaxis or by the intravenous injection of antibody or antigen alone, was studied in the rabbit. Emphasis was placed on timing the events in inflammation. The inflammatory response was studied at three levels of experimentation: microscopic observation of the microvasculature and supporting tissue in the ear chamber, monitoring of the intravascular cellular elements during the reaction, and gross and microscopical study of ear chamber and visceral tissues secured just before death or sacrifice of the rabbit.The first cell affected appeared to be the leukocyte. This was supported by observations in the ear chamber, white blood cells adhering to endotheliallining cells of the microvessels, and a drop in the leukocyte count. Then the platelet count dropped quickly, and within 10 min emboli and thrombi were observed in the microvessels of the ear chamber. Later events in the inflammatory sequence included the swelling of endothelial cells, migration of leukocytes, and appearance of microhemorrhages in the ear chamber. Pathology was more marked in passive and active anaphylaxis than when either antibody or antigen alone was injected intravenously.Histological examination of tissue from various visceral organs and the ear chamber secured just before the death or sacrifice of the rabbit, showed inflammatory changes consistent with those noted in the ear chamber during all phases of the response.     

Nasal mast cell response to natural allergen exposure

A redistribution of mast cells into the epithelium and towards the mucosal surface was previously observed during the allergy season in individuals allergic to birch pollen. We have therefore attempted to investigate in greater detail the role of mast cells in mucosal allergy by the study of the morphological and biochemical changes that occur in the nasal mucosa of allergic individuals during natural allergen exposure. An activation of the intraepithelial mast cells was indicated by the observation of ultrastructural signs of a secretory activity. We also found that the normal strong correlation between mast cell numbers and histamine content in the nasal mucosa was absent in specimens taken during allergen exposure, which was interpreted as a result of a release of histamine from the mast cells with the appearance of a transient, non-mast cell pool of tissue histamine. Furthermore, the histamine content of the nasal mucosa during the pollen season was strongly correlated to the severity of symptoms experienced by the patients. These observations provide additional evidence that mucosal mast cells have a pathogenetic role in continuous allergic airway disease.     

Effect of lung tissue on the inhibitory actions of isoprenaline, theophylline, disodium cromoglycate and PGE1 on antigen-induced mast cell degranulation.

Isoprenaline, disodium cromoglycate and PGE1 poorly inhibit antigen-induced degranulation of sensitised rat peritoneal mast cells, but in the presence of chopped rat lung their inhibitory activities were markedly enhanced. The chopped lung preparation had no effect on degranulation in the absence of an inhibitor and did not enhance the weak inhibitory potency of theophylline. Lung tissue suspensions pretreated with isoprenaline released a factor into the supernatant which enhanced the action of isoprenaline on peritoneal mast cells. The activity of this supernatant factor was destroyed by boiling for 5 min. Supernatant fluid from untreated lung tissue did not itself reduced antigen-induced degranulation or enhance the inhibitory potency of isoprenaline.     

The Anti-Anaphylactic Action of Tiaramide Hydrochloride

Tiaramide hydrochloride (THC) is a new basic, non-steroidal, anti-flammatory drug. Its anti-anaphylactic action has been investigated using rat mast cells. It was found that THC exerts a strong inhibitory action on antigen-induced and compound 48/80-induced histamine release from rat peritoneal mast cells in a fluorometric assay. Compound 48/80-induced vasodilatation in rat skin is inhibited by prior intradermal injection of THC, as measured by blueing of skin due to intravascular Evans blue dye. THC also inhibits radio-labeled serotonin release from compound 48/80-challenged rat mast cells. In these experimental systems a similar action was exerted by disodium cromoglycate, but higher drug concentrations were needed. Further studies are needed to determine the exact mode of action of this drug and its eventual clinical use in the field of allergic diseases.     

Pharmacological characterization of mouse ear PCA

Effects of some antiallergic agents on homologous passive cutaneous anaphylaxis (PCA) in mouse ear were investigated by means of assessing the amount of extravasated dye. Antihistamines (chlorpheniramine and diphenhydramine) and antiserotonins (methysergide and cyproheptadine) suppressed mouse ear PCA significantly. In contrast, an antagonist of slow reacting substance of anaphylaxis (SRS-A) (FPL 55712) and an inhibitor of SRS-A synthesis (AA-861) did not suppress the reaction. beta-Adrenergic stimulants (isoproterenol and salbutamol) and theophylline, which elevate cyclic AMP (cAMP) levels, also suppressed mouse ear PCA significantly. The antiallergic agents, N(3',4'-dimethoxycinnamoyl)anthranilic acid(N-5') and ketotifen suppressed mouse ear PCA significantly, but disodium cromoglycate (DSCG) failed to suppress the reaction.     

Anti-allergic activities of a new benzopyranopyridine derivative Y-12,141 in rats.

Passive cutaneous anaphylaxis (PCA) mediated in rats by IgE-like antibodies against egg albumin or the benzylpenicilloyl determinant was inhibited in a dose-dependent manner by intravenous treatment with Y-12,141; the ED50 was 0.09--0.2 mg/kg. The inhibitory effect of Y-12,141 ON PCA was about 5 times as potent as that of disodium cromoglycate (DSCG). Oral treatment with Y-12,141 resulted in the inhibition of PCA, showing an ED50 of 2.5 mg/kg. This action of Y-12,141 on PCA was considered to be due to the inhibition of the release of allergic mediatros from mast cells in a manner similar to DSCG. The results suggest that Y-12,141 may have an anti-allergic activity.     

Eustachian tube function associated with histamine-induced and ragweed-induced rhinitis

Nasal allergies may contribute to Eustachian tube dysfunction and chronic middle ear problems. In exploring this association further, Eustachian tube function was measured in ten ragweed-allergic and eight non-allergic patients undergoing repetitive nasal provocation. Anterior nasal provocation was done using paper disks impregnated with either histamine or aqueous ragweed allergen. Increasing concentrations of the provocative agent were placed on both inferior nasal turbinates until moderate symptoms of rhinitis developed. Eustachian tube function was evaluated using the 9-step inflation-deflation tympanometric test before and immediately after each nasal challenge. Eustachian obstruction developed in 4 of 38 non-allergic ears during histamine nasal provocation. With ragweed nasal challenge, 9 of 42 allergic ears developed Eustachian tube obstruction. Four allergic ears gained Eustachian tube function despite being obstructed before the challenge. The observed changes in ear function for both groups were not significant due to variability in Eustachian response. At the concentrations which initiated symptoms of rhinitis, nasal provocation with histamine or ragweed did not consistently obstruct the Eustachian tube. We conclude that mild symptoms of allergic rhinitis may not cause significant Eustachian tube obstruction.     

Effect of topical corticosteroids on seasonal increases in epithelial eosinophils and mast cells in allergic rhinitis: a comparison of nasal brush and biopsy methods

BACKGROUND: Nasal brushing and nasal biopsy are well-tolerated sampling techniques. Seasonal grass pollen-induced rhinitis is characterized by epithelial mast cell infiltration and seasonal increases in both epithelial and sub-mucosal eosinophils. OBJECTIVE: To compare the ability of the nasal brush and nasal biopsy techniques to detect natural seasonal increases in eosinophils and mast cells, and to assess the influence of topical corticosteroid. METHODS: Nasal brush samples and nasal biopsies were collected from 46 grass pollen-sensitive seasonal rhinitis patients before the grass pollen season and at the peak of the pollen season following 6 weeks' treatment with either fluticasone propionate aqueous nasal spray (200 microg, twice daily) or placebo nasal spray. RESULTS: Placebo patients showed seasonal increases in epithelial eosinophils both with nasal brushing (P < 0.0001) and biopsy (P < 0.001). Epithelial mast cell numbers also increased during the pollen season as detectable by brushing (P < 0.0001) and biopsy (P < 0.03). Changes in cell numbers measured by nasal brushing correlated with those observed with nasal biopsy, both for eosinophils and mast cells (P < 0.05). Sub-mucosal eosinophils but not mast cells also increased during the pollen season (P < 0.002). Nasal brushing and biopsy revealed that fluticasone treatment inhibited seasonal increases in epithelial eosinophils (P < 0.00001) and epithelial infiltration by mast cells (nasal brushing P < 0.00001 and nasal biopsy P < 0.01). Fluticasone also inhibited seasonal increases in sub-mucosal eosinophils (P < 0.001) and significantly reduced nasal symptoms (P < 0.001). CONCLUSION: Nasal brushing harvests sufficient inflammatory cells from the surface of the nasal mucosa to be used in lieu of nasal biopsies in observation of the effect of drugs on the nasal epithelium.     

Histamine secretion from mast cells treated with chlortetracycline (aureomycin): a novel calcium ionophore

The novel calcium ionophore chlortetracycline (CTC) induced histamine secretion (≤90%) from isolated rat peritoneal mast cells in a pH and dose-dependent fashion. The process was dependent on exogenous calcium ions and was inhibited by extremes of temperature and metabolic blockers. The release was rapid, being essentially complete within 1 min, but the half-life of the process varied inversely with the concentration of the ionophore. In contrast to receptor-mediated ligands, but in keeping with other ionophores, the activated state induced by CTC did not decay with time. The secretion was effectively inhibited, according to the concentration of the ionophore, by disodium cromoglycate and other anti-allergic or cyclic AMP-active drugs. These results confirm our previous contention that these agents do not act on receptor-mediated calcium-channels. CTC induced a significant (≤50%) release of histamine from enzymically dispersed rat mesenteric mast cells but was essentially inactive against isolated mast cells from the mesentery or lung of the guinea-pig. These results extend our former observations on the functional heterogeneity of mast cells and show that, in common with other secretagogues, ionophores may exhibit selectivity in their mode of action.     

Action of the human lymphokine histamine releasing factor on mouse peritoneal mast cells

Histamine releasing factor (HRF)--a human lymphokine--has been shown previously to release histamine from basophils in vitro. In this paper we show that HRF acted across the species barrier and released histamine from mouse peritoneal mast cells. This response was dose-dependent. Mast cells from both sensitized and non-sensitized mice were equally susceptible to the action of HRF. We observed synergistic action of HRF with specific allergen (ovalbumin) or HRF with anti-IgE antibody in releasing histamine from mast cells. Preincubation of mast cells with calcium ion chelating agent ethylenediaminetetraacetic acid (EDTA) or disodium cromoglycate induces only a small inhibition of histamine release caused by HRF. We conclude that histamine release from mouse peritoneal mast cells can serve as an in vitro test for the assay of human HRF.     

Intra-nasal beclomethasone dipropionate and intra-nasal sodium cromoglycate: a comparative trial

Ten patients with either seasonal allergic or perennial rhinitis were treated with intra-nasal beclomethasone dipropionate B.P. (Beconase) and nine comparable patients were treated with sodium cromoglycate B.P. (Rynacrom). The beclomethasone dipropionate was administered as 50 μg per puff into each nostril three times a day and the sodium cromoglycate as one capsule insufflated into each nostril four times a day. Treatments were allocated on a randomized basis and each patient received a course of treatment lasting 2 weeks during the summer of 1973 when the pollen counts were high. Utilizing patient daily symptom diary cards, physician's assessment and by examination of the nasal mucosa prior to and at the end of treatment, it was concluded that both intra-nasal beclomethasone dipropionate and intra-nasal sodium cromoglycate effect a reduction in the symptoms associated with rhinitis. No side effects of importance were noted, nor were there any adverse changes observed in the state of the nasal mucosa.