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A simple technique to produce spray-dried porous particles for inhalatory administration was developed. The particles were produced using water as solvent, Sodium Cromoglycate as model drug and ammonium bicarbonate as pore forming agent. A central composite design was employed to study the influence of the: pore-forming agent concentration (in the drug aqueous solution fed to the spray dryer) and air inlet temperature on: process yield and powder properties. The powder particle size distribution, moisture content, densities and estimated aerodynamic diameters were studied. Also, particles morphology, hygroscopicity, surface area, in vitro aerosolization properties, dissolution rate and stability were evaluated for some selected samples. In addition, a novel friability test was proposed for mechanical resistance evaluation of the porous materials. A pore forming agent concentration of 1.25% (w/w) and an air inlet temperature of 170 °C were the optimal process parameters to produce porous particles suitable for inhalatory administration. The process yield was high and it was demonstrated that the particles were free of ammonium bicarbonate. The porous powder, obtained by a simple and scalable technique, exhibited low tap density, good stability even at long storage periods (12 months), appropriate mechanical resistance, high initial dissolution rate and excellent aerosolization performance. Fil: Gallo, Loreana Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina Fil: Ramírez Rigo, María Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina Fil: Bucala, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Universidad Nacional del Sur. Departamento de Ingeniería Química; Argentina

Background Recurrent cow's milk (CM) aspiration is often associated with gastroesophageal reflux in infants and toddlers and it seems to be implicated in the etiology of different inflammatory lung disorders. This study aimed to investigate ex vivo the impact of CM aspiration on human airways and whether treatment with beclomethasone dipropionate (BDP) or sodium cromoglycate (SCG) may prevent the potential CM-induced airway hyperresponsiveness (AHR). Methods Human isolated bronchi were contracted by electrical field stimulation (EFS10Hz) to mimic the contractile tone induced by the parasympathetic activity and challenged with CM, fat/lactose-free CM, or human breast milk (HM). The effect of pre-treatment with beclomethasone dipropionate (BDP) and sodium cromoglycate (SCG) was also investigated on the AHR induced by CM. Results After a 60 min-challenge with CM 1:10 v/v and fat/lactose-free CM 1:10 v/v, ASM significantly (P ​, Graphical abstract Image 1, Highlights • Cow's milk aspiration seems to be associated with some inflammatory lung diseases. • Cow's milk aspiration induces human airway hyperresponsiveness. • Beclomethasone and sodium cromoglycate protect against cow's milk hyperresponsiveness in vitro. • Inhaled sodium cromoglycate might be suitable in children at risk of cow's milk aspiration.

When the expected effect of an inhaled drug is not achieved, the cause could be poor inhalation technique and consequently a low pulmonary dose. A simple in vivo test to evaluate the pulmonary dose would be a benefit. This study evaluates the relative and systemic bioavailability following inhalation of nebulized sodium cromoglycate (SCG) in healthy subjects. Blood samples were collected during 240min and urine was collected in two portions, up to 6h post-inhalation. Two exposures were performed and comparisons based on the quantification of drug in plasma and urine by a high-performance liquid chromatography (HPLC) procedure were done. In one of the exposures, a pulmonary function test was performed to study if an expected effect of increased absorption could be detected. There was a good correlation between the two exposures shown in the plasma concentrations, but not in the urine analyses. The forced exhaled volume manoeuvres were associated with a higher Cmax and plasma concentrations up to 60min post-inhalation (P

Objective A study was made to assess the proportion of 17-year-old students who consider themselves to have allergic rhinoconjunctivitis and to find out how they treat themselves. Method The study was performed outside the pollen season in 1993 and 1994 and 5,938 first-year secondary school students in eight different cities were asked to answer a questionnaire during class. Results A total of 1,458 students (24%) claimed that they suffered from allergic rhinoconjunctivitis after being given a description of the disease. Sixty-five percent had had symptoms for 3 or more years and most of the sufferers, 71% had had symptoms during the spring and/or summer. In 32% of the sufferers, the causative agent was unknown. Seventy-six percent (n = 1,103) of the sufferers treated themselves with drugs. The most commonly used drugs for a systemic effect were nonsedating antihistamines and for a local effect, sodium cromoglycate. Of those who used nasal drugs (sodium cromoglycate and/or steroids, n=545), only 14% used them daily, 51% always when having symptoms, and 35% occasionally when having symptoms. The reasons for not using nasal sprays daily were inconvenience and embarrassment. Twenty-five percent had bought the drug over-the-counter in 1992, the first year when allergy drugs could be purchased without a prescription. The use of over-the-counter treatment increased in the following year to 33% ( P Conclusion We conclude that many young people perceive themselves as having allergic rhinoconjunctivitis and that the treatment can be much improved for the group as a whole.

The influence of sodium-cromoglycate (cromolyn) on the binding and ingestion of sheep erythrocytes (SRBC) by elicited rat peritoneal macrophages (M phi) was studied using unsensitized SRBC. SRBC sensitized by homologous IgG or by IgM and complement as target cells. Preincubation of M phi with the drug (1 nM/1-2 mM/1) markedly enhanced both binding and ingestion of uncoated SRBC. The IgG-related increment in binding and phagocytosis was not significantly influenced by the drug. When target cells were coated by IgM and complement cromolyn pretreatment was ineffective. Preincubation of M phi by bovine brain gangliosides (BBG) diminished the cromolyn-induced enhancement of target cell binding and phagocytosis. When SRBC were pretreated by BBG, an increase of binding and phagocytosis was observed. These data suggest that cromoglycate may enhance the capacity of M phi to bind erythrocytes via ganglioside structures. Coating SRBC by complement components appears to interfere with binding of erythrocytes to M phi ganglioside receptors.

Background Sodium cromoglycate was first introduced as an inhaled treatment for bronchial asthma in the late 1960s. Initially, it was presented as 20 mg of sodium cromoglycate (SCG) combined with 0.1 mg of isoprenaline sulphate in a capsule which was inhaled using a Spinhaler. Sodium cromoglycate without isoprenaline sulphate was introduced shortly afterwards and, subsequently, further formulations have been introduced. These include a 1% aqueous solution containing 20 mg SCG for nebulization, a metered dose inhaler (MDI) delivering I mg SCG per actuation, an MDI delivering 5 mg SCG per actuation and an MDI delivering I mg of SCG and 0.1 mg of salbutamol per actuation. The most commonly used form at present is the MDI delivering 5 mg per actuation.

Although the Spinhaler has been available for many years as a delivery device for sodium cromoglycate powder, the quantity of powder delivered to the lungs and the optimal mode of inhalation for this device have remained largely unknown. Lung deposition of 20 mg sodium cromoglycate powder (labelled with the radionuclide 99m Tc) from the Spinhaler has been measured in 10 healthy volunteers who inhaled by four carefully controlled inhalation modes, involving fast (120 l min −1 ) and slow (60 l min −1 ) peak inhaled flow rates, holding the head in the normal and tilted-back (60° to the horizontal) positions, and breath-holding pauses of 0 and 10 s. Inhalation at 60 l min −1 significantly ( P −1 . Among the inhalation modes tested, delivery to the lungs was optimised (mean 17.1% of the dose) when powder was inhaled at 120 l min −1 , with the head in the normal position, and with 10 s breath-holding.

Repeated bronchial histamine challenges before, during, and after the birch pollen season were performed in 22 allergic patients with bronchial hyperreactivity (BHR) treated for 6 wk with sodium cromoglycate (SCG), 20 mg, four times a day, or placebo in a double-blind, randomized group comparison. Clinical assessments of the asthmatic symptom score and peak expiratory flow revealed less symptoms and less use of bronchodilators in the SCG group. Responsiveness to histamine was significantly increased in the placebo group after 14 days with high pollen counts. After the season there was an immediate return to preseasonal value. There was no change in responsiveness in the SCG group, demonstrating significant protection against pollen-induced increase of BHR. The results support the hypothesis that inhibition of mediator release, which is demonstrated for SCG, leads to a reduction of the nonspecific BHR.

The qualitative and quantitative determination of large anionic solutes, including the drug sodium cromoglycate, by an ion-pair high-performance liquid chromatographic technique using alkylbenzyldimethylammonium chlorides as pairing ions is described. The method provides a sensitive and selective assay for the solutes examined in both simple aqueous solutions and in complex biological fluids, and requires no pre-extraction step. Retention mechanisms are discussed.

A double-blind placebo controlled study of sodium cromoglycate, beclomethasone dipropionate and salbutamol by inhalation was designed to test their effect on respiratory symptoms and changes in ventilatory capacity in cotton mill workers. All three drugs showed some beneficial effect. Salbutamol was the most effective drug studied, in all groups of workers. Beclomethasone dipropionate was also significantly effective particularly in workers with byssinosis or exertional dyspnoea. Sodium cromoglycate was the least effective of the three. Possible mechanisms of action of these drugs are described.

I. Shapiro G, Konig P. Cromolyn sodium: a review. Pharmacotherapy 1985;5(3):156-70. 1 Bernstein L. Cromolyn sodium in the treatment of asthma: coming of age in the United States. J ALLERGY CLIN hdMUNOL 1985;76:381-88. 3. Munro-Ford R. Disodium cromoglycate in the treatment of seasonal and perennial asthma. Med J Aust 1969;2(11):53740 4. Hobday JD. The effect of disodium cromoglycate on asthma m children: a double-blind study on seven asthmatics during the pollen season. Aust Paediatr J 1970;6( 1): 14-6. 5. Engstrom I. Evaluation of Lomudal treatment in children. Stand J Respir Dis 1977;101:49-56. 6. Howell JBL. Altounyan REC. A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet 1967;2:539-42. 7. Blumenthal MN, Schoenwetter WF, MacDonald FM, McHugh RB. Cromolyn in extrinsic and instrinsic asthma. J ALLERGY CLIN IMMUNOI. 1973;52(2):105-14. 8. Koch GG, Amara IA, Davis CiW. Gtlhngs iI’\, lt IC~I~U at some statistical methods for covarianc:: anaiyw .?t .xtea~~rizal data. Biometrics 1982;38:563-95 9. Mantel N. Chi-square tests with one degree \I[ frcedo~;: cxtenSIons of the Mantel-Haenszel proc~iurc J pi!> I% 3:PB h(X)700. 10. Schoeffel RE, Anderson SD, Lindsay DA. Stri~:m! crornoglycate as a pressurized aerosol I Vicrorn) m eul,ni\;~-ir!duced asthma. Aust NZ J Med 1983:13(2):1~7-61 11. Bundgaard A, Bach-Mortensen N. Schmidt ,A ‘The effect of sodium cromoglycate delivered by Spmhaler ;md by pressurized aerosol on exercise-induced asthma rn chtifirc:i CIi;l Allergy 1982; I2(6):60 I-5. 12. So SY, Yu DYC. Sodium cromoglycate dehver*;d b> prcsrurized aerosol in the treatment of ;tsthma Cim Allergy 198 I; I 1(5):479-82. 13. La1 S. Malhotra SM. Gribben MD. Compun~un oi sodmm cromoglycate pressurized aerosol and powder in the treatment of asthma. Clin Allergy 1982;12(2) 1~7.2(!i

Equations have been developed relating the tensile strengths T N m −2 of certain powders to the packing fraction ϱ f , mean diameter d metres, and average shape coefficient α, of the particles. These are log T = 6.56 log (αϱ f d −1 ) − 40.39 with a correlation coefficient 0.83 for calcium carbonate and log T = 6.77 log (αϱ f d −1 ) − 41.39 with a correlation coefficient 0.80 for sodium cromoglycate. The equations apply to cohesive powders with particles between 1 and 15 μm mean diameter.

Pathogenesis of food allergy and review of drugs: antihistamines, sodium cromoglycate, β-adrenoreceptor agonists, inhibitors of arachidonic acid metabolites, calcium channel antagonists

Sixteen adult asthmatic subjects in a clinical steady state were included in the study. On day 1, after baseline assessment of spirometry (FEV 1 , FEV 1 /FVC, FEF 25–75 ), they underwent three to four consecutive inhalation tests using twofold increasing doses of histamine to measure the provocative concentration causing a fall in FEV 1 of 20% (PC 20 ). Baseline FEV 1 was back to ±5% of the initial assessment before each histamine inhalation test (HIT). On days 2, 3, and 4, after baseline spirometry which confirmed that FEV 1 was within 10% of initial day 1 assessment, placebo-lactose (P) or 40 mg of sodium cromoglycate (SCG) were nebulized in a double-blind randomized 4.3.1. two-treatment crossover study design. Ten minutes later, spirometry was repeated and followed by an HIT. Baseline spirometry was not significantly different on each day or after P and SCG. There was no statistical difference between the geometric means of the three or four PC 20 's done on day 1, indicating that there is no tachyphylaxis induced by repeated HIT. There was no statistical difference between mean PC 20 after P (0.52±3.3 (SD) mg/ml), after SCG (0.50±3.2), and of the three to four HIT done on day 1 (0.40±3.6). We conclude that in asthmatic subjects SCG has no acute bronchodilator effect and does not alter the response to inhaled histamine.

β-Adrenergic bronchodilators can prevent the development of exercise-induced asthma (EIA). To investigate the duration of this effect, we determined the time at which the protective effect of salbutamol diminished significantly in six subjects. All had stable asthma known to be triggered by exercise. Following a control exercise test, identical tests were repeated weekly at various times (1–6 hours) after inhalation of 200 μg of salbutamol. Significant protection ( A further exercise test was performed after inhalation of 1 mg of reproterol, at the time when salbutamol no longer afforded significant protection. There was a significantly smaller fall in peak expiratory flow rate after exercise ( P There was no relationship between the degree or duration of protection from EIA and the bronchodilator effect of the drugs, the age and sex of the subjects, the length of asthma history or severity of base-line EIA, except perhaps the requirement for regular treatment with a steroid aerosol or sodium cromoglycate.

In recent years there has been increased awareness of the importance of preventative therapy in the management of asthma (1). In the U.K. inhaled corticosteroids are the principal prophylactic drug used for the treatment of adult asthma whereas sodium cromoglycate is less commonly prescribed in adults. Recently, nedocromil sodium, a nonbronchodilator antiasthmatic drug, was introduced as a prophylactic treatment for asthma. This overview of nedocromil sodium will attempt to answer the following questions about the drug: Does it possess anti-inflammatory properties? Can it attenuate the response to different bronchoconstrictor stimuli in man? How do the pharmacological properties of nedocromil sodium compare with those of sodium eromoglycate? Do the results of currently published therapeutic trials suggest a place for nedocromil sodium in the management of adult asthma?

The safety evaluation of cromolyn sodium (sodium cromoglycate) included 20 separate toxicity studies in rhesus, cynomolgus and stump-tailed macaques, baboons, and squirrel monkeys. The studies were performed to help evaluate the safety for humans of the use of the compound by dry powder inhalation for the treatment of asthma and by application to the eyes and nose in the treatment of conjunctivities and rhinitis. A previously unreported vascular lesion, the occurrence of which in these studies was responsible for a considerable extension of the safety evaluation program, was eventually shown to be unrelated to cromolyn sodium treatment. The only significant toxic effect was renal damage due to blockage of tubules with precipitated compound. This was confined to injection studies, where large multiples of the therapeutic dose were given. These studies demonstrate an adequate safety margin between the therapeutic dose of cromolyn sodium and the lowest dose needed to produce this effect. No cromolyn sodium-induced toxicity was seen in studies using the prescribed therapeutic routes.

The first long-term study of sodium cromoglycate, reported in 1972, demonstrated the effectiveness of sodium cromoglycate in controlling asthma. The trial had various limitations, but more recent trials have been designed so that they overcome some of these problems. Results of these trials validate the results obtained in the first long-term trial.

28 children with chronic asthma (15 in Denver and 13 in London) completed a 12 wk double-blind trial of treatment with sodium cromoglycate (cromolyn sodium), theophylline, and a combination of both. The three regimens were administered, each for 4 wk, in random sequence as part of a collaborative investigation of the relative efficacy of the two antiasthmatic agents. Cromoglycate was administered by inhalation in standard doses of 20 mg q.i.d. Theophylline dosage was individualised with the assistance of serum-theophylline measurements and averaged 6 mg/kg/dose q.i.d. (range 3·8-8·5 mg/kg/dose). Peak expiratory-flow rates measured twice daily on all patients averaged 75% of that predicted during cromoglycate administration, 79% during theophylline, and 81% during the combined-drug regimen (P

Serum pepsinogen concentrations rose more rapidly and to higher levels in adult sheep infected with Ostertagia circumcincta and treated orally with the mast cell stabilising agent sodium cromoglycate than they did in adult sheep infected with the parasite which remained untreated. Sodium cromoglycate did not affect the serum pepsinogen concentrations or abomasal pH in uninfected sheep.

Specific IgE complexes and symptoms of asthma and eczema were produced in two allergic patients by oral challenge with food allergen. Both symptoms and IgE complexes could be prevented by pre-treatment with oral sodium cromoglycate. The IgE complexes can fix complement and may therefore provide the vehicle of the "late" responses seen in immediate hypersensitivity. The central role of gut sensitivity is emphasised by the protection afforded by sodium cromoglycate both when given acutely, against the effects of an oral challenge, and when given continuously for asthma and eczema due to food allergy.

Foods which provoked migraine in 9 patients with severe migraine refractory to drug therapy were identified. The patients were then given either sodium cromoglycate or placebo orally in a double-blind manner, with foods previously identified as provocants. Sodium cromoglycate exerted a protective effect, thus confirming that it can prevent a hypersensitivity mechanism as well as the symptoms of migraine. Immune complexes were not produced in those patients who were protected by sodium cromoglycate. These observations confirm that a food-allergic reaction is the cause of migraine in this group of patients.

The possible importance of leukotrienes (LTs) as mediators of bronchoconstriction was examined in two normal volunteers. When inhaled in aerosols, synthetic LTC and LTD were equally effective in limiting expiratory flow at low lung volumes, with little reduction in forced expiratory volume. After LT inhalation the forced expiratory manoeuvres ended in bouts of coughing. Pretreatment with sodium cromoglycate did not modify these responses, whereas the SRS-A antagonists FPL 55712 and FPL 59257 abolished the cough response and partly inhibited the bronchoconstriction in both subjects.

Intal drops (sodium cromoglycate) relieved symptoms of vernal conjunctivitis in all the 19 patients we studied, reducing the need for steroids although the response varied. Intal was also effective in all 11 patients with acute or subacute seasonal allergic conjunctivitis, but in only 4 of 11 patients with mild chronic conjunctivitis associated with atopy. No side-effects were noted other than mild irritation in some cases.