Inhaled Disodium Cromoglycate Research Articles

Have inadequate delivery systems hampered the clinical success of inhaled disodium cromoglycate? Time for reconsideration

Importance of the field: Disodium cromoglycate (DSCG) fits with the perception of a safe drug, but conclusions from questionable meta-analyses reduced its use. In addition, drug delivery aspects, such as hygroscopicity and the poor performance of delivery systems, were not considered to be important determinants of therapeutic failures.Areas covered in this review: Drug delivery aspects and parameters affecting lung deposition and distribution, important parameters for therapeutic efficacy, are addressed. In addition, the distribution and ratio of mast cell tryptase and chymase-positive phenotypes in the lungs and their role in the prostaglandin and leukotriene pathway are discussed.What the reader will gain: Information on why in vitro data are an excellent tool to understand better therapeutic failures associated with the moisture sensitivity of DSCG and the difficulty in handling and operating DSCG delivery systems in a therapeutically reliable way.Take home message: Pharmacological efficacy of DSCG has been demonstrated in animals and humans. If the drug is delivered to the site of inflammation in an effective dose, a reliable therapeutic effect can be expected. DSCG has extra properties and potential unspecific antiviral properties and may offer new therapeutic treatment aspects for asthma and viral-induced bronchiolitis in early childhood.

The New Role of Disodium Cromoglycate in the Treatment of Adults with Bronchial Asthma

Viral infection of the respiratory tract in patients with asthma is one of the most frequent causes of exacerbation of asthmatic symptoms. Disodium cromoglycate (DSCG) is a commonly used anti-asthmatic medicine with many beneficial biochemical and physiological effects. The purpose of this study was to investigate the efficacy of DSCG against colds when used in clinical practice. A questionnaire survey to determine the efficacy of DSCG was undertaken in 220 adult patients with asthma (81 male, 139 female; mean age: 54.1 +/- 13.7 years and 60.1 +/- 12.7 years, respectively) from April to September 2004 at the Miyatake Asthma Clinic. The duration of DSCG inhalation therapy was not less than 5 years in more than half of the patients. The mean daily DSCG dose at the time of the questionnaire survey was 40mg/day in over 50% of all patients. After DSCG was added to inhaled corticosteroid (ICS) combination therapy, 56.4% of the patients rated their condition as "improved", and 66.4% of the patients felt that the frequency of colds they had caught had decreased while DSCG was added to ICS. DSCG inhalation therapy is a useful additional treatment following ICS to alleviate asthma symptoms, and to prevent colds in adult patients with asthma.

Separation of bronchoconstriction from increased ventilatory drive in a nonhuman primate model of chronic allergic asthma

The relationship between allergen-induced ventilatory drive and bronchoconstriction was investigated in dust mite-sensitive cynomolgus macaques periodically exposed to low doses of aerosolized antigen for up to 5.5 yr. Initially, the animals responded to aerosolized dust mite allergen at a concentration of 350 arbitrary units (AU)/ml with simultaneous increases in lung resistance (RL) and respiratory rate (RR). With time, RL and RR became differentially sensitive to allergen provocation. At the end of the study period, aerosolized allergen at a concentration of 15 AU/ml doubled RR without increasing RL. When mechanically ventilated to maintain tidal volume, higher concentrations of allergen could be delivered, and RL increased. Inhaled disodium cromoglycate and intravenous diphenhydramine attenuated the increase in RR, indicating that allergen-induced release of histamine and activation of H(1) receptors mediated the response. Inhaled beta-adrenergic agonists attenuated the RR response to dust mite and to direct histamine provocation. These results demonstrate that chronic periodic allergen challenge increases the allergic sensitivity of histamine-dependent reflexes controlling ventilatory drive. Activation of these reflexes is independent of overt bronchoconstriction, but can be inhibited by beta-adrenergic agonists, indicating that beta-adrenergic agonists exert their effect independent of bronchodilation.

Pulmonary tumour embolism

24 Jacobs B, Young NL, Dick PY, et al. Canadian Acute Respiratory Illness and Flu Scale (CARIFS): development of a valid measure for childhood respiratory infections. J Clin Epidemiol 2000; 53: 793–99. 25 Yang M, Rasbash J, Goldstein H, Barbosa M. MLwiN macros for advanced multilevel modelling, version 2.0. London: Multilevels Models Project, Institute of Education, University of London, 1999. 26 Goldstein H, Healy M, Rasbash J. Multilevel time series models with applications to repeated measures data. Stat Med 1994; 13: 1643–55. 27 Tasche MJA, Uijen JHJM, Bernsen RMD, Jongste JC, van der Wouden JC. Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review. Thorax 2000; 55: 913–20. 28 Majeed A, Moser K. Ageand sex-specific antibiotic prescribing in general practice in England and Wales in 1996. Br J Gen Pract 1999; 49: 735–36. 29 Stott NCH. Management and outcome of winter upper respiratory tract infections in children aged 0-9 years. BMJ 1979; 1: 29–31. ARTICLES

Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systematic review

BACKGROUNDDisodium cromoglycate (DSCG) is included in the BTS guidelines on the treatment of asthma for use in children, but is now used only infrequently. We have identified and interpreted the...

A partial involvement of histamine in ultrasonically nebulized distilled water-induced bronchoconstriction in guinea-pigs.

1. Inhalation of ultrasonically nebulized distilled water (UNDW) can induce bronchoconstriction only in asthmatics, but mechanisms of the response are not well known. We recently reported a guinea-pig model of UNDW-induced bronchoconstriction (UNDW-IB) in which UNDW induces bronchoconstriction when UNDW is inhaled 20 min after a challenge with aerosolized ovalbumin (OA) in passively sensitized, anaesthetized and artificially ventilated guinea-pigs. 2. To elucidate the role of histamine in the UNDW-IB, we examined the effects of antihistamines, diphenhydramine hydrochloride (DH) and chlorpheniramine maleate (CP), and measured histamine content in bronchoalveolar lavage fluid (BALF) in the animal model. 3. DH in doses of 0.1, 1.0 and 10 mg kg(-1) and CP in doses of 0.01, 0.1 and 1.0 mg kg(-1) administered intravenously 15 min after the OA challenge partially reduced the UNDW-IB at 1 and 2 min after the UNDW inhalation in a dose-dependent manner. Histamine content in BALF recovered 10 min after the UNDW inhalation following the OA provocation was significantly increased compared with that after saline inhalation and before the UNDW inhalation following the OA challenge. 4. Intravenous atropine in a dose of 0.5 mg kg(-1) or inhaled disodium cromoglycate in concentrations of 1 and 10 mg ml(-1) did not alter the UNDW-IB. 5. These results suggest that histamine is involved in part in the UNDW-IB in our animal model.

The efficacy of inhaled disodium cromoglycate and glucocorticoids.

Clinical & Experimental AllergyVolume 26, Issue s4 p. 8-17 The efficacy of inhaled disodium cromoglycate and glucocorticoids K-H. CARLSEN, Corresponding Author K-H. CARLSEN Voksentoppen, Center of Asthma and Allergy in Children, Oslo, Norway, SwedenProfessor Kai-Hakon Carlsen, Voksentoppen, Center of Asthma and Allergy in Children, Ullveien 14, 0394 Oslo, Norway.Search for more papers by this authorK. LARSSON, K. LARSSON National Institute for Working Life, Solna, SwedenSearch for more papers by this author K-H. CARLSEN, Corresponding Author K-H. CARLSEN Voksentoppen, Center of Asthma and Allergy in Children, Oslo, Norway, SwedenProfessor Kai-Hakon Carlsen, Voksentoppen, Center of Asthma and Allergy in Children, Ullveien 14, 0394 Oslo, Norway.Search for more papers by this authorK. LARSSON, K. LARSSON National Institute for Working Life, Solna, SwedenSearch for more papers by this author First published: June 1996 https://doi.org/10.1111/j.1365-2222.1996.tb00662.xCitations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume26, Issues4June 1996Pages 8-17 RelatedInformation

Questionnaire Survey on Asthma Management of Japanese Allergists II. Treatment methods

ABSTRACT A questionnaire on the treatment of asthma was sent to 586 physicians. They consisted of specialists authorized by the Japanese Society of Allergology and councillors of the society who were treating patients with bronchial asthma. Of the total of 306 (52%) respondents, 241 replied to questions relating to adult asthma and 129 to questions relating to childhood asthma (including duplicate replies). For acute treatment, methods most commonly selected by physicians were, in increasing order of popularity, for adults: parenteral aminophylline, oxygen inhalation, parenteral steroids and parenteral adrenaline; for schoolchildren (6–16 years): parenteral aminophylline, inhaled β-stimulant, oxygen inhalation, inhaled β-stimulant + disodium cromoglycate (DSCG), parenteral steroids; and for infants (≤ 5 years): inhaled β-stimulant, parenteral aminophylline, oxygen inhalation, inhaled β-stimulant + DSCG and parenteral steroids. For maintenance treatment, methods most commonly selected by physicians were, in increasing order of popularity, for adults: oral administration of sustained-release theophylline, inhaled steroids and DSCG inhalation; for schoolchildren (6–16 years): DSCG inhalation, oral administration of sustained-release theophylline, oral administration of antiallergic agent preparation and (β-stimulant + DSCG inhalant; and for infants: DSCG inhalation, oral administration of sustained-release theophylline, oral administration of antiallergicagent preparation and β-stimulant + DSCG inhalant. The questionnaire results clearly showed that different drugs were selected for the treatment of asthma in adults, schoolchildren and infants.

Effect of Disodium Cromoglycate on Ventilation and Gas Exchange During Exercise in Asthmatic Children With a Postexertion FEV1 Fall Less Than 15 Percent

The purpose of this study is to evaluate the effect of disodium cromoglycate (DSCG) on gas exchange and ventilation during incremental exercise in asthmatic children with an FEV1 fall less than 15 percent from the baseline after the exercise. Seventeen children (aged 8 to 14 years) with a history of mild to moderate asthma but no clinical and spirometric evidence of exercise-induced asthma (EIA) underwent two maximal exercise tests in a randomized order: test A without premidication and test B after inhalation of DSCG, 40 mg. To evaluate the effect of DSCG on normal airways, nine healthy children performed the same exercise protocol. Pulmonary function was normal at rest and after treadmill exercise test (the mean postexercise fall in FEV1 was 5.9 percent in test A and 1.5 percent in test B). Gas exchange, minute ventilation (VE) and heart rate (HR) were monitored during running in both tests. In the asthmatic subjects, there were no differences in oxygen uptake (VO2), carbon dioxide output (VCO2), and VE at rest between the two tests. During exercise, VE, VO2, VCO2, and energy cost (EC[O2 ml.kg-1.m-1]) of running in the asthmatic subjects were significantly lower in test B than in test A (analysis of variance, p < 0.01) for comparable work rates. Maximal minute ventilation (VEmax) was significantly higher in test A (46.9 +/- 14.6[+/- SD]L.min-1) than in test B (43.2 +/- 14 L. min-1; p < 0.05). We found no significant effect of DSCG on gas exchange and ventilation during exercise in the healthy children (VEmax 47.8 +/- 25 and 48.4 +/- 25 L.min-1 in test A and B, respectively). In conclusion, premedication with DSCG appears to decrease the ventilatory cost of exercise in asthmatic children who do not present a substantial fall in FEV1 after an exercise test without pretreatment.

Effect of inhaled disodium cromoglycate and albuterol on energy cost of running in asthmatic children

The purpose of this study is to evaluate the effect of disodium cromoglycate and albuterol on energy cost of running, gas exchange, and ventilation during maximal exercise in children with exercise-induced asthma (EIA). Twelve children (7.1-15.5 years old) with a history of mild to moderate asthma and EIA performed three maximal exercise tests on a treadmill: 1) test A, without premedication; 2) test B, after premedication with inhaled disodium cromoglycate (DSCG) (40 mg); 3) test C, after premedication with inhaled albuterol (200 micrograms). The energy cost of running was calculated at each minute of exercise. None of the children were limited by dyspnea during the run. The post-exercise fall in FEVi after test A was greater than 20% for each child, the mean fall being 32.8 +/- 11.6%, in comparison with 12.6 +/- 8.9% after test B (P less than 0.001) and 2.5 +/- 5.3% after test C (P less than 0.001). There was no difference in the baseline oxygen uptake for the three tests. Maximum oxygen uptake (VO2 peak) decreased from 43.9 +/- 7.7 mL/min/kg in test A to 37.7 +/- 6.0 mL/min/kg in test B (P less than 0.01) and 39.1 +/- 7.2 mL/min/kg in test C (P less than 0.05). Ventilatory anaerobic threshold in tests B and C was significantly lower than in test A (P less than 0.01). Ventilation (L/min) and energy cost of running (O2 mL/kg/m) were significantly lower in tests B and C than in test A at comparable times. Running time was longer in B and C (P less than 0.05) with respect to A.(ABSTRACT TRUNCATED AT 250 WORDS)

A COMPARISON OF THE EFFECTS OF AZELASTINE AND DISODIUM CROMOGLYCATE ON BRONCHIAL HYPERRESPONSIVENESS IN CHILDREN WITH ASTHMA

We studied the effects of azelastine and disodium cromoglycate on bronchial responsiveness in 26 asthmatic children, using histamine inhalation challenge.We divided the subjects into three groups. For 12 weeks, the 1st group of patients inhaled 20mg of disodium cromoglycate 4 times daily, the 2nd group took oral administrated 2mg of Azelastine twice daily and the 3rd group had no antiallergic drugs. Histamine inhalation challenges were performed before and at the end of treatment period. There was no statistical difference between the results obtained before and at the end of treatment in the group which didn't have antiallergic drugs. But the threshold of histamine had significantly increased after treatment of DSCG and Azelastine (p<0.05, p<0.01 respectively).Our results suggested that not only the inhaled disodium cromoglycate but also the administration of azelastine had the effect of attenuating the bronchial hyperresponsiveness of asthmatic children.

Failure of inhaled disodium cromoglycate aerosol to prevent exercise-induced pulmonary hemorrhage in racing quarter horses.

Failure of inhaled disodium cromoglycate aerosol to prevent exercise-induced pulmonary hemorrhage in racing quarter horses.

Disodium cromoglycate compared with beclomethasone dipropionate in juvenile asthma

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.

A controlled trial of ketotifen in exercise-induced asthma

We studied 17 patients in a double-blind controlled trial to see if ketotifen, a new oral mast-cell stabilizing agent, would protect against bronchoconstriction induced by exercise on a treadmill. In addition eight of the patients also completed exercise tests without previous medication and again after inhalation of disodium cromoglycate (DSCG). The greatest amount of bronchoconstriction was caused by exercise without preliminary treatment. There was less bronchoconstriction after ketotifen, but this was no better than a placebo. DSCG provided significant protection. We were unable to confirm previous reports that ketotifen is as effective as DSCG in preventing exercise-induced asthma.

A controlled trial of ketotifen in exercise-induced asthma

We studied 17 patients in a double-blind controlled trial to see if ketotifen, a new oral mast-cell stabilizing agent, would protect against bronchoconstriction induced by exercise on a treadmill. In addition eight of the patients also completed exercise tests without previous medication and again after inhalation of disodium cromoglycate (DSCG). The greatest amount of bronchoconstriction was caused by exercise without preliminary treatment. There was less bronchoconstriction after ketotifen, but this was no better than a placebo. DSCG provided significant protection. We were unable to confirm previous reports that ketotifen is as effective as DSCG in preventing exercise-induced asthma.

Bronchial and intravenous provocation tests with indomethacin in aspirin-sensitive asthmatics.

In an attempt to elucidate the mechanisms involved in analgesic-induced asthma, I performed bronchial and intravenous challenge tests with indomethacin in 5 aspirin-sensitive asthmatics. Bronchial challenge with less than 2 mg of indomethacin elicited bronchoconstriction that developed immediately in most cases, reached its macimum at a mean time of 64 min, and was over within 2 to 4 h. The time sequence of the reaction after intravenous challenge was similar to that after bronchial challenge, except that to obtain a comparable degree of bronchoconstriction it was necessary to administer at least twice the inhaled dose. Inhalation of disodium cromoglycate during bronchoconstriction inhibited the reaction within 8.6 +/- 5.7 min, regardless of the route of challenge. This suggests that sequential mast cell degranulation with liberation of chemical mediators is the mechanism responsible for bronchoconstriction in analgesic-induced asthma.

A study of the chronic toxicity of inhaled disodium cromoglycate in the squirrel monkey

A chronic inhalation toxicological study of disodium cromoglycate (cromolyn sodium, intal) was performed in the squirrel monkey, Saimiri sciureus. Each of five experimental groups consisted of three male and three female monkeys. Groups I and II were exposed 6 hr/day, 7 days/week, for 1 year to aerosols containing a disodium cromoglycate blend in approximate concentrations of 0.5 and 0.05 mg/liter of air, respectively. Group III was similarly exposed to an aerosol containing 0.01 mg of lactose/liter of air. Group IV animals served as chamber controls, and the room controls (Group V) were maintained in the animal holding room throughout the study. A comprehensive toxicological evaluation of the monkeys was carried out prior to and throughout the study. At appropriate intervals observations were made of physical appearance, behavior, weight gain, and ophthalmoscopic appearance; electrocardiograms, systolic blood pressure measurements, hemograms, blood biochemical profiles, and urinalyses were also obtained. At termination, necropsies were conducted, and organ weights were determined. A variety of staining techniques was employed in the histopathological examination of tissues. Special attention was given to heart, kidney, and lung structures and to vascular and nerve tissues. Bone marrow smears and the distribution and morphology of mast cells in the lung were studied. Ultrastructural studies, using the electron microscope, were made of the lungs. No changes that could be attributed to the action of disodium cromoglycate were seen in any parameter. A special absorption study in five monkeys showed that the Group I animals absorbed about 60 times the recommended human dose.

Inhalation of polymyxin B as a bronchial provocation method

With the exception of allergen inhalation, current bronchial provocation tests do not elicit a reaction identical to an asthmatic attack because the first stage of the latter — degranulation of mast cells — does not occur. In order to detect bronchial hyperreactivity and to determine the role of mast cells, polymyxin B — a histamine releasing agent — was administered by inhalation to 49 asthmatic patients and the resulting bronchospasm compared with that induced by histamine and exercise. Inhalation of disodium cromoglycate (Intal®) inhibited the response to polymyxin B. Polymyxin B probably acts on mast cells in lung tissue. Inhalation of polymyxin B appears to be useful as a method for detection of bronchial hyperreactivity.

Airways narrowing in exercise in normal subjects and the effect of disodium cromoglycate.

In a group of 26 young healthy adults, with no history of chest disease or atopy, post-exercise airways narrowing was demonstrated in both smokers and non-smokers. Inhalation of disodium cromoglycate (DSCG) on 5 occasions over 24 hours significantly reduced the post-exercise airways narrowing. The reduction was greater in the non-smokers, to the extent that post-exercise ventilatory tests showed no decline in DSCG-treated non-smokers. Sixteen subjects exhibited post-exercise rhonchi. After DSCG inhalation, post-exercise rhonchi were heard in only 8 subjects. The maximum mid-expiratory flow rate (MMEF) appeared to be a more sensitive measure of post-exercise change than either the forced expiratory volume 1st second (FEV 1 ) or the specific airways conductance (SG aw ).

Plasma levels and urinary excretion of disodium cromoglycate after inhalation by human volunteers

The plasma levels, rate of urinary excretion, total urinary excretion and the amount deposited in the mouth were measured after human volunteers had inhaled disodium cromoglycate (DSCG) (the disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane) from capsules in the Spinhaler ®. Immediately after inhalation 30% to 50% of the dose was deposited in the mouth and was recovered by means of mouth washings; in clinical use this proportion of the dose would be swallowed. The powder which reached the lung was absorbed rapidly, the plasma levels reached a peak concentration 20 min after inhalation, and the mean maximum rate of urinary excretion occurred during the first hour. Total urinary excretion of DSCG over 8 hr amounted to a mean of 4.2% of the dose (SD: ± 1.9). This indicated a total deposition in the lungs of about 7.5% (range 5–10%) of the dose of DSCG.