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Background Lichen planus (LP) is a common skin disorder of unknown aetiology that affects the skin, mucous membranes and nails. Although metal allergies have been implicated in the development of oral LP (OLP), the contribution of these allergies to nail LP (NLP) has yet to be studied in detail. Objective To elucidate the link between metal allergy and NLP. Methods We retrospectively analysed 115 LP patients with respect to the contribution of metals to either NLP or OLP. We also attempted to detect the specific metals involved in these nail lesions. Results Of the 79 patients that received a metal patch test (PT), 24 (30%) were positive for at least one of the metal compounds tested. Notably, the prevalence of positive reactions to metals in the NLP patients was significantly higher as compared with the OLP patients (59% vs. 27%, P

Conflicting results have emerged from studies using oral and rectal disodium cromoglycate (DSCG) in inflammatory bowel disease. In the present double-blind study, 43 patients with active ulcerative proctosigmoiditis received either placebo (n = 22) or 600 mg DSCG (n = 21) rectally as enemas for eight weeks. Assessment was made from clinical investigations, endoscopy, laboratory tests, biopsies, and diary cards. No statistically significant differences in bowel frequency, rectal bleeding, general well-being, abdominal pain, and severity and extent of the disease were found between the groups during the study. There was no significant change in the histologic parameters. No side-effect was encountered. It is concluded that DSCG did not improve symptoms or inflammatory changes in ulcerative proctosigmoiditis.

The in vitro effect of disodium cromoglycate (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 sensitized mast cells. DSCG in concentrations 3 x 10(-7) M to 3 x 10(-4) M was added to the mucosal specimens before antigen challenge. Mast cell degranulation in the sensitized specimens challenged with egg white was 38%. Mast cell degranulation in sensitized specimens treated with DSCG before and during antigen challenge was reduced to 2% at a concentration of 3 x 10(-5) M of DSCG (P=0.006) and to 28% at a concentration of 3 x 10(-6) M (P=0.027). No significant reduction of mast cell degranulation was seen at concentrations of 3 x 10(-7) M and 3 x 10(-4) M. The results support a role for DSCG in the treatment of gastrointestinal allergy.

The effect of SCG powder (Lomudalr, Intalr) intranasally in vasomotor rhinitis has been studied on 49 adult volunteers in a double-blind cross-over study during 13 weeks in January--April 1973. The dose of SCG was 40 mg/day. Although a substantial number of results were obtained, no significant difference between the effects of SCG and placebo treatment, on variables measured, was detected. However, some patients experienced relief with, and preferred, the treatment with SCG. The results from this investigation are discussed in comparison with those from other studies including patients with vasomotor rhinitis.

Aims To compare the plasma concentrations of disodium cromoglycate (DSCG) following various inhalation procedures in healthy volunteers. Methods Nine healthy subjects inhaled 2 mg of aerosol, 20 mg of nebuliser solution only, 20 mg of nebuliser solution mixed with isotonic saline, or 20 mg of nebuliser solution mixed with saline and procaterol, a β2-adenoceptor agonist, on separate occasions 2–3 weeks apart. Plasma concentrations of DSCG were determined by high-performance liquid chromatography (h.p.l.c.). Results The peak plasma concentrations of DSCG were 1.5±0.7 (range 0.4–2.4) ng ml−1 in the aerosol group, 8.8±6.2 (range 5.3–19.9) ng ml−1 in the nebuliser solution only group, 17.2±16.3 (range 5.0–38.6) ng ml−1 in the nebuliser solution plus isotonic saline group, and 24.5±11.9 (range 10.2–44.9) ng ml−1 in the nebuliser solution plus saline and procaterol group. Thus subjects who used the nebuliser had markedly higher plasma concentrations of DSCG than subjects who used the aerosol inhaler. Conclusions These findings may have important implications for the evaluation of inhalation treatment with DSCG for bronchial asthma.

A series of N-(4-isoxazolylthiazol-2-yl)oxamic acid derivatives was synthesized and tested on the passive cutaneous anaphylaxis (PCA) model in rats to verify its potential antianaphylactic activity. These compounds were prepared by reaction of an appropriate bromoacetylisoxazole with thiourea to give the corresponding aminothiazole and subsequent condensation with an oxalic acid monoester chloride to yield, following the usual process, the oxamic acid derivatives. Most of the new compounds exhibited, by intraperitoneal route in rats, a very potent antianaphylactic activity on PCA response, higher than that of the reference compound disodium cromoglycate (DSCG). The new derivatives, in contrast with DSCG, were effective on PCA even by oral route. The most interesting derivative of the new series was N-[4-(3-methyl-5-isoxazolyl)-2-thiazolyl]oxamic acid 2-ethoxyethyl ester (49), which was also active and more potent than DSCG in experimental models involving either IgE- or IgG-mediated anaphylactic responses at bronchopulmonary level.

Inhalation of inert particles may in susceptible subjects with bronchial asthma result in reflex bronchoconstriction mediated through the vagal nerves. A case of severe asthmatic reaction with bronchial spasm in a 60-year-old man with intrinsic asthma after inhalation of disodium cromoglycate powder (Lomudal) during long-term treatment is reported. The mechanism is considered to be reflexogenic. Because of the variability in individual susceptibility during long-term treatment, inhalation therapy should always be given with close attention to asthmatic exacerbations.

Summary A double-blind, randomized-group comparative trial was conducted to assess the therapeutic effect of cromolyn solution on atopic dermatitis in young children (< 3 yr old). Topically applied cromolyn solution was found to be very effective, improving dermatitis, itching and sleep disturbance, with no untoward effects.

Allergic rhinitis (AR) is a common disease in many developed countries. Its prevalence is estimated at ≈10–20% of the general population Understanding the pathogenesis and mechanisms that lead to allergic nasal disease and, thus, to the symptomatology of allergic rhinitis provides a framework for a rational therapy in this disorder. Treatment has to focus primarily on the symptomatology of the patient, taking into account the time, duration and severity of the disease. In the position paper on the treatment of allergic rhinitis of the European Academy of Allergology and Clinical Immunology,1 guidelines to treat seasonal and perennial allergic rhinitis are presented. Table 1 will help to make a rational choice. Table 1. Guidelines for the treatment of seasonal and perennial allergic rhinitis Oral antihistimine Nasal antihistimine Nasal steroids Nasal decongestant Ipratropic bromide Nasal DSCG DSCG, disodium cromoglycate. Rhinorrhoea ++ ++ +++ 0 ++ + Sneezing ++ ++ +++ 0 0 + Itching ++ ++ +++ 0 0 + Blockage + + +++ ++++ 0 + Eye symptoms ++ 0 ++ 0 0 0 Onset of action 1 h 15 min 12 h 5–15 min 15–30 min Variable Duration 12–24 h 6–12 h 12–48 h 3–6 h 4–12 h 2–6 h

The clinical effect of disodium cromoglycate was compared with placebo in patients with perennial allergic rhinitis. The results of a double-blind cross-over trial in 17 patients suggest that insufflation with 10 mg disodium cromoglycate four times a day has no better effect than placebo. No significant differences between the side effect of disodium cromoglycate and placebo were noted.

Summary Seven patients with respiratory symptoms after welding were examined. Five had occupational asthma caused by fumes from manual metal are stainless steel welding. The detailed clinical results of two patients with repeated challenge tests are reported. One patient was nonatopic and had earlier had contact dermatitis due to chromium. He experienced a non-immediate type of asthmatic reaction after welding stainless steel. The other patient was atopic and showed an immediate-type reaction. Both reactions were repeated in the second provocation lest after about 2 years. In addition both disodium cromoglycate and beclomethasone pretreatments inhibited the reaction of the two patients, but a placebo medication did not. A remarkable amount of chromium and nickel are detected in the fumes released during stainless steel welding but not in the fumes from mild steel welding, with which all provocation tests were negative. The chromium or the nickel in welding fumes might be the aetiological factor of the reaction.

In vitro models of anaphylaxis such as the release of mediators from the mast cell can do more than identify compounds with intrinsic anti-allergic activity; they have the potential for development of a detailed profile of activity that may be compared and contrasted in several ways to that of disodium cromoglycate. These parameters include effects upon (a) immunologic versus nonimmunologic release, (b) IgE- versus IgG-provoked release, (c) timing of compound addition relative to challenge, (d) repeated administration (presence or absence of tachyphylaxis), (e) wash-out of agent (reversibility), and (f) other granulocyte models relative to the mast cell. Use of in vitro models of anaphylaxis in this way allows an early judgment to be made about the extent to which a new compound presents a novel anti-allergic profile.

In this investigation, a double-blind, cross-over trial of sodium cromoglycate in 23 patients with perennial rhinitis was carried out. An improvement in symptoms was found in actively-treated patients, and a greater preference was expressed for active treatment. There was no relationship between response to sodium cromoglycate and the results of allergological investigation. It is conclcuded that therapeutic trial of sodium cromoglycate is worth considering in patients with perennial rhinitis, irrespective of the results of RAST and intracutaneous skin tests.

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.

Summary In a double-blind controlled crossover trial of inhaled disodium cromoglycate and beclomethasone dipropionate in juvenile asthma, beclomethasone produced higher therapeutic scores but significantly so in only two indices–wheeze-free days and morning peak flow rates. Combined treatment offered no advantage over beclomethasone alone. No side-effects were noted. The findings confirm other studies of cromoglycate and a steroid aerosol (betamethasone 17-valerate) but disagree with the only other comparative trial of cromoglycate and beclomethasone, in which both were found equally effective.

Fourteen boys with a mean age of 12.2 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.

The aim of this study was to compare the efficacy and side effects of budesonide and disodium cromoglycate (DSCG) in seasonal allergic rhinitis. In a double-blind, double-dummy comparative study, 43 patients with seasonal allergic rhinitis were either treated with budesonide (200 micrograms b.d.) or DSCG (5.2 mg 5 times daily). After a 1 week run-in period treatment was given for 3 weeks. The patient scorings for nasal secretion, nasal itching, sneezing bouts and total nasal symptoms were significantly different between the treatment groups during the whole treatment period. The scorings for nasal blockage were significantly different during the last 2 weeks of treatment. All differences were in favour of budesonide treatment. The patients' assessment of the treatment favoured budesonide (P less than 0.02). Side effects were few and mild, but one patient from the budesonide group stopped treatment because of headache.

Summary The acute effect of ethanol inhalation on ventilatory capacity was studied in a group of six healthy volunteers and the results were compared to those obtained after the inhalation of a saline solution. There was a significant decrease in flow rates on partial expiratory flow-volume (PEFV) curves up to 90 min after ethanol inhalation. FEV1 values did not change significantly, either after ethanol or saline aerosol. Pretreatment with atropine did not prevent the acute reductions in flow rates in comparison with the reductions without atropine. Pretreatment with disodium cromoglycate (DSCG) considerably diminished the acute reductions of flow rates caused by ethanol inhalation. These results suggest that ethanol in some persons may act, at least partly, through releasing mediators with bronchoconstrictive action.

Neutrophil chemotactic factor (NCF) is a slight acidic macromolecule which is released into the circulation of asthmatic individuals following antigen provocation and an exercise task. It also appears in late asthmatic reactions with a time course of appearance which precedes the second fall in FEV1. The release of NCF was inhibited by prior administration of disodium cromoglycate (DSCG) suggesting its possible mast cell origin.

The effect of Syrijet applied disodium cromoglycate (DSCG) on mast cell degranulation and on gingivitis was investigated in rhesus monkeys. Mast cell counts were obtained by tracing representative areas from specially stained tissue sections and visually counting mast cells per unit area. Results revealed that while the drug inhibited mast cell degranulation, this was not associated with any detectable change in gingivitis in the time period studied. D.S.C.G. should provide an invaluable tool for the continued investigation of the role of mast cells in gingivitis.

The effect of the anti-allergic drug disodium cromoglycate (DSCG) on immediate and late responses to anti-human IgE was examined in thirteen healthy subjects. DSCG, 250 micrograms, applied intradermally together with anti-IgE had no effect on the immediate flare and weal response, whereas the following late phase response, 1-24 hr, was attenuated by 15% (P less than 0.05, at 6 hr P less than 0.01). This effect varied between individuals (P less than 0.01) and was reproduced in a second trial in DSCG-responders and non-responders (P less than 0.01, n = 8). The results support the view that DSCG has no effect on the immediate mast cell derived response in human skin but can inhibit the development of late reactions. This mechanism might account for some of the anti-allergic effects of the drug.

Summary The ability of disodium cromoglycate (DSCG) to block allergic responses in the nasal airways was investigated in two ways. The effect of DSCG on antigen-induced airways resistance changes in sensitive subjects was investigated in the laboratory. DSCG in a dose of 10 mg applied to each nostril was shown to block the expected reaction in 71 % of subjects and a 1 mg dose in 47%. Protection was conferred against antigen challenge for a period of about 6 hr by the 10 mg dose. A clinical trial of DSCG (10 mg) in seasonal allergic rhinitis was carried out using a double-blind cross-over design. Analysis of the results showed significant DSCG protective effects against lower respiratory tract symptoms and a significant antihistamine sparing effect. Analysis of part of the trial period when antigen challenge was uniformly high showed significant DSCG protective effects against sneezing, nasal discharge and nasal obstruction. Nasal application of DSCG is considered to be a promising alternative therapeutic approach in allergic rhinitis.

Summary Fourteen patients with extrinsic type bronchial asthma had pulmonary ventilation, lung volume and gas transfer measurements at rest and on exercise, carried out during a control period and again at 2 weeks and 12 months whilst on disodium cromoglycate. A significant improvement in forced expiratory volume, vital capacity and the ratio of residual volume to total lung capacity and in the exercise gas transfer, was observed at 12 months. The improved pulmonary function measurements agree with the clinical assessment of the improvement obtained in these patients whilst on disodium cromoglycate.

Summary The urinary excretion of disodium cromoglycate (DSCG) was used as an index of the amount reaching the lungs in nine normal subjects and in fifteen patients with obstructive airways disease. Vital capacity (VC), forced expiratory volume in one second (FEV1) and peak inspiratory flow rate (PIF) through the spinhaler were also measured. The amount of DSCG detected in urine varied considerably. It was correlated with the physiological measures and with age. The usual DSCG excretion pattern was of a declining excretion rate from 0 to 3 hr following the dose, but certain individuals showed a rise to the second hour, before a fall occurred in the third hour. The occurrence of a rise was associated with a very low reading in the first hour, which in turn was associated with severe obstructive airways disease. Overall, the lowest excretion rates, and the poorest scores for VC, FEV1 and PIF were recorded in a sub-group of five chronic bronchitics, who were also the oldest group. In one chronic bronchitic no drug was detected. The highest excretion rates and best physiological scores were recorded in the normal subjects, who were also the youngest group.

Summary Sixteen workers, from a platinum refinery, with respiratory disease were tested with solutions of complex salts of platinum and ten gave immediate prick test reactions to concentrations of 10−4−10−6and immediate nasal reactions in seven out of eleven tested to concentrations of 103−10−8. Occupational-type exposure inhalation tests to the dust from mixtures of 40 mg of the platinum salt with 1 kg of lactose gave immediate asthmatic reactions in eight and in one of these a late reaction, all also giving immediate prick test reactions. The asthmatic reactions were inhibited by disodium cromoglycate. In two with negative prick tests, late asthmatic reactions were elicited. The occupational-type exposure test provides a safe, acceptable procedure for etiological diagnosis.

Disodium cromoglycate was applied before patch testing in patients with contact allergy to propipocaine hydrochloride, nickel and formaldehyde. The responses obtained were mitigated to a high degree when compared with similar effects, due to corticoids.

The reaction of disodium cromoglycale with five cationic dyes: crystal violet, Janus green, methylene blue, methyl green, and safranine, was investigated. Spectroscopic shifts indicated that at low concentration (0.01 mM) all these dyes were able to form complexes (ion paris) with the cromoglycale anion. In addition, the complexes formed by crystal violet and Janus green were extractable into chloroform.

SYNOPSIS A double blind study using disodium chromoglycate and a placebo was undertaken during the pollen season in Perth. 7 children with severe asthma were investigated and most showed improvement in symptoms, by day and night 5 of the 7 showed improvement in respiratory function studies at the end of the period on disodium cromoglycate. It is concluded that this compound is of value in the treatment of the asthmatic child.

A new series of N-(1H-tetrazol-5-yl)-6-phenyl-2-pyridinecarboxamides was prepared to determine the effects of substituents on the benzene and pyridine rings on antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) assay after oral administration. One member of this series, N-(1H-tetrazol-5-yl)-4-methyl-6-[4-(methylamino)-phenyl]-2- pyridinecarboxamide (231), has an ED50 value of 0.8 mg/kg po and is 85 times more potent than disodium cromoglycate (DSCG) on intravenous administration. Further evaluation of 231 as a clinically useful antiallergic agent is in progress.

A group of (2-carboxy-1,4-dihydro-4-oxoquinolyl)oxamic acids (5) containing the oxamic acid group in the 5,6, or 7 positions were synthesized and investigated for antiasthma activity as indicated by the passive cutaneous anaphylaxis (PCA) reaction in rats. Also synthesized and investigated were two (2-carbosy-1,4-dihydro-4-oxobenzo[h]-quinolyl)oxamic acids (9 and 10). Several of the compounds synthesized (viz. 5e, 5f, and 10) showed activity in the PCA test approximately 25 times that shown by disodium cromoglycate (1), as measured by the ID50 doses.

Selected derivatives of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole, a new heterocyclic ring system, and their S-oxides have been prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. Several of the compounds show intravenous potencies similar to or greater than that of disodium cromoglycate, the most potent being 6,7-dimethyl-9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole and its 4,4-dioxide.

Structural modification of 3,4-dihydro-4-oxoquinazoline-2-carboxylic acid leading to ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate, a new prototype with oral antiallergy activity of the disodium cromoglycate type, is described. This prototype is 10 times more potent than disodium cromoglycate in the rat passive cutaneous anaphylaxis test. Structure-activity studies indicate that a carboxylic acid moiety directly attached to the 2 position of the pyrimidine ring is most favorable for intravenous activity while esters of this acid are preferred for oral activity. The oral activity of ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate (ED50 = 3 mg/kg) places this ester among the more potent orally active antiallergy agents reported to date.

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.