An unexpected reaction towards disodium cromoglycate

In recent years disodium cromoglycate has become a useful tool in handling allergic rhinoconjunctivitis and asthma. Very few side effects have been reported, and the drug's working mechanism is thought to be its "mast cell stabilizing" effect. A patient with an immediate type I reaction to DSCG is reported on.     

Local disodium cromoglycate is ineffective in ulcerative proctosigmoiditis

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.     

Studies on the mechanism of tachyphylaxis to disodium cromoglycate.

The tachyphylaxis to disodium cromoglycate's (DSCG) inhibition of antigen-induced histamine release is readily demonstrable utilizing passively sensitized rat lung fragments. This tachyphylaxis to DSCG is evident whether or not calcium is present during drug preincubation. An attempt to relate the mechanism of tachyphylaxis to the DSCG-induced release of an endogenous cellular inhibitory material was unsuccessful insofar as could be demonstrated by an effect on mediator release.     

Effect of disodium cromoglycate on asthmatic reactions to alcoholic beverages

Eleven asthmatic patients with a history of asthma with or without rhinitis following the ingestion of alcoholic drinks were challenged by oral ingestion of the suspected drink, and some with equivalent amounts of ethyl alcohol. Asthma was provoked in six cases, four having falls in the FEV₁ of more than 15%. Three of the latter studied in detail gave immediate asthmatic reactions to the alcoholic beverage, but not to the ethyl alcohol tested by oral ingestion, and in one case by administration through a naso-gastric tube. Pre-treatment by inhalation of disodium cromoglycate inhibited the asthmatic reactions to the alcoholic beverages.     

Assay of specific IgE antibodies to disodium cromoglycate in serum from a patient with an immediate hypersensitivity reaction

A 29-year-old man with pollen allergy had experienced immediate adverse reactions, such as itching of the eyes, rhinitis, wheezing, and general urticaria, after using disodium cromoglycate (DSCG) eye drops. The local symptoms were reproducible, and skin tests were strongly positive. With serum from the patient, a RAST was developed for the assay of IgE antibodies. The uptake on RAST disks was 6% of the total activity added, which was a significantly higher level than was found in sera from 35 randomly selected blood donors or in sera from 25 patients tolerating DSCG. By addition of DSCG to the patient's serum, 95% of the binding to paper disks could be inhibited. The induction of specific IgE antibodies was proposed to be a result of a combination of electrostatic and hydrophobic interaction of DSCG and a protein carrier. The substance would thus act as a hapten without any covalent binding to the carrier. DSCG may serve as a model for other nonreactive low-molecular-weight substances suspected to elicit type I-like adverse reactions.     

The mechansim of tachyphylaxis to ICI 74,917 and disodium cromoglycate.

Pre-incubation in vitro of sensitised peritoneal mast cells for 10 min with either ICI 74,917 (10-5 M) abolished the ability of either drug to inhibit histamine release when subsequently presented to the cells at the same time as antigen. In the case of disodium cromoglycate, tachyphylaxis was abolished by washing the cells after pre-incubation with the drug. The failure to abolish tachyphylaxis to ICI 74,917 was due to the high pre-incubation concentration employed, as at lower concentrations (10-8 M) tachyphylaxis to ICI 74917 was readily abolished by washing. Tachyphylaxis to these anti-allergic agents may be related to a physical blocking of drug receptor sites on or in mast cells.     

An antiallergic activity of disodium cromoglycate unrelated to mast cell activation

The pharmacological effects of disodium cromoglycate (DSCG) were studied in rats during the development of reactions to various allergens or carrageenin. DSCG (10 mg/kg and 100 mg/kg, i.v.) showed pronounced inhibitory effects on type I and type III (passive Arthus) allergic reactions. An immunological degranulation of mast cells and a significant decrease in tissue histamine content were observed in type I allergic reactions but not in type III allergic reactions characterized by an apparent infiltration of neutrophils. An antihistaminic agent, promethazine (1 mg/kg, i.v.) was effective only against type I allergic reactions and totally ineffective against type III allergic reactions. Thus, the results obtained above strongly suggest that DSCG exhibits at least two mechanisms of antiallergic action; one is related to mediator release from mast cells and the other is unrelated to mast cell activation.     

Specific inhibition of allogeneic reactions with disodium cromoglycate

Milligram amounts of disodium cromoglycate (DSCG) inhibit allogeneic responses in mixed lymphocyte culture (MLC) reactions, but do not affect cell viability or suppress lymphocyte responses to either phytohemagglutinin (PHA) or pokeweed (PKW) mitogens. Preincubation of lymphocytes with DSCG is without effect, indicating that membrane binding is an unlikely explanation for inhibition. The HLA-DR tissue typing of cells in the presence of optimal MLC-inhibitory doses of DSCG is normal suggesting that MLC-reactive lymphocytes are not denied recognition of these antigens. Timed studies demonstrate that DSCG must be present continuously during the induction period, for removal of DSCG after 16 hr culture restores MLC reactivity and addition of the drug after 48 hr is without effect. Both natural killing (NK) and cell mediated lympholysis (CML) assays proceed normally in the presence of optimal MLC-inhibitory concentrations of DSCG; however, CML reactions are eliminated by the addition of drug during cytotoxic T cell priming. Background CML reactivity also disappears when lymphocytes are continuously cocultured in DSCG, implying that such killing cannot be attributed to NK activity. DSCG is said to inhibit allergic reactions by impeding calcium flux across mast cell membranes, thereby preventing degranulation, but other mechanisms are required to explain the selective effects on in vitro lymphocyte reactivity.     

Uptake of disodium cromoglycate in obstructive airways disease

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.     

Enigma of disodium cromoglycate action on mast cells.

In rat peritoneal mast cells, disodium cromoglycate showed no inhibitory effect on histamine release values if the cells were preincubated with the drug for 40 min prior to stimulation with antigen, compound 48/80 or ATP. If the drug was added simultaneously with antigen or a low dose of compound 48/80, a repression of histamine release occurred. No such effect was noted if ATP was employed as histamine liberator.     

Clinical trial of topical disodium cromoglycate in vernal kerato-conjunctivitis

The results of a double blind placebo-controlled clinical trial of topical administration of disodium cromoglycate drops to one eye and placebo drops to the other eye in the treatment of vernal kerato-conjunctivitis in twenty-two patients indicates that the drug has a significant therapeutic effect. Patients vary in the degree of their response, but nearly all are helped. From long-term uncoded administration of the drug to both eyes in sixty-one patients, it has been found that supplementation with topical steroid may be required for short periods to control acute exacerbations of the disease. However, it is now possible to reduce or avoid the use of steroids in many cases, and thus greatly reduce the dangers of steroid-induced glaucoma or steroid-enhanced herpetic keratitis. No side effects have been noted other than occasional irritation apparently due to thiomersal, the bacteriostatic agent used in the trial preparation. This irritancy, which was not detected in preliminary animal experiments, or in trials in volunteers, occurred only during periods of exacerbation of vernal disease. The findings suggest that there is an important Type I hypersensitivity phenomenon in the pathogenesis of the disease, and although other mechanisms are probably also involved, modification of this Type I reaction is of therapeutic benefit.     

Inhibition of C5a-induced basophil degranulation by disodium cromoglycate

Injection of purified porcine C5a into 24-hr basophil-rich cutaneous basophil hypersensitivity sites in the dose range 10^–12–10^–10 moles/site produced cutaneous basophil anaphylaxis (CBA). The H₁ anti-histamine antagonist mepyramine, given orally (3.0–30 mg/kg), inhibited the vasopermeability, but not the basophil degranulation, characteristic of CBA. The antiallergy agent disodium cromoglycate (DSCG), administered intravenously (3.0–30 mg/kg), inhibited vasopermeability and basophil degranulation. DSCG inhibition of mast cell degranulation was not important in the inhibition of CBA, since intact mast cells were found to be depleted at basophil-rich sites and absent at C5a-induced CBA sites from animals treated with DSCG.C5a at 10^–11 moles/site also induced vasopermeability and mast cell degranulation in normal guinea pig skin. Vasopermeability, but not mast cell degranulation, was inhibited by mepyramine at 30 mg/kg p.o. However, DSCG at 10 mg/kg i.v. failed to inhibit either the vasopermeability or the mast cell degranulation of this reaction. These results indicate that C5a induces the degranulation of both basophils and mast cells in the guinea pig, and that C5a-induced degranulation of basophils, but not mast cells, is inhibited by DSCG.