Alan M. Edwards

Respiratory pathophysiologic responses: The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma

BACKGROUND Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.Abstract Background: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. Objective: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. Methods: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at ~30 L/min or ~70 L/min. Percent decreases in FEV 1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. Results: Mean (± SD) allergen-induced decrease in FEV 1 was 5.4% ± 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV 1 after faster inhalation of CS with 12.6% ± 11% ( p 1 and skew values for the two breathing maneuvers were significantly correlated. Conclusion: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Oral and topical sodium cromoglicate in the treatment of diffuse cutaneous mastocytosis in an infant

Diffuse cutaneous mastocytosis (DCM) is a rare, severe, variant of cutaneous mastocytosis. The authors report the case of a male infant who developed maculae and maculopapulae on his legs and abdomen when aged 3.5 months, which spread to all body surfaces within weeks. Diagnosis of DCM was made at the age of 6 months when he had developed extensive bullous eruptions, generalised pruritus, flushing and abdominal pain. Treatment was started with oral dimethindine maleate. At the age of 18 months, oral sodium cromoglicate (SCG) was introduced. At the age of 23 months, additional treatment was started with a cutaneous emulsion containing 4% SCG. Continued treatment with oral dimethindine maleate, oral SCG with the dose maintained at 25 mg/kg/day, and SCG 4% cutaneous emulsion applied two to four times daily has resulted in a steady improvement of symptoms and skin appearance.

Oral and inhaled sodium cromoglicate in the management of systemic mastocytosis: a case report

IntroductionMastocytosis is a rare disease consisting of a group of disorders characterized by a pathologic increase in the number of mast cells in one or more organ system. Treatment is symptomatic. Oral sodium cromoglicate (SCG) is the only treatment licensed for the treatment of mastocytosis. In this case we report how in a mastocytosis patient being treated with H1 and H2 antihistamines, and oral sodium cromoglicate, the addition of inhaled sodium cromoglicate resulted in further improvement. This is the first report of this use of the drug in this disease.Case presentationThe subject is a Caucasian woman aged 40 years. Symptoms of mastocytosis began when she was aged 13 years, but the diagnosis was not made until after her first pregnancy aged 33 years. Symptoms improved with H1 and H2 antihistamines, and oral sodium cromoglicate, but it required the addition of inhaled sodium cromoglicate to produce further improvement, specifically in the symptoms of bone pain, fatigue and headache. Doses of oral sodium cromoglicate had to be increased if challenged with a food to which the subject was sensitive. Doses of inhaled sodium cromoglicate had to be increased during the menstrual period.ConclusionsPatients suffering from the rare disease of mastocytosis have symptoms affecting many body systems. Symptoms result from the release of inflammatory mediators from mast cells. Sodium cromoglicate, a drug that reduces the release of mediators from mast cells, is effective in controlling gastrointestinal symptoms, but less effective in those affecting other body systems. In this case report we have shown that the addition of inhaled sodium cromoglicate controls the symptoms of bone pain, fatigue and headache and also that the doses have to be increased during the menstrual period.

The effect of 4% sodium cromoglicate cutaneous emulsion compared to vehicle in atopic dermatitis in children – A meta-analysis of total SCORAD scores

Abstract An emulsion containing 4% sodium cromoglicate (4% SCG emulsion) has been developed for the treatment of atopic dermatitis in children. We have conducted a meta-analysis of the primary outcome measure (the change in SCORAD score) used in randomized clinical trials (RCTs) with this product. We conducted a search of standard using the keywords, sodium cromoglicate, cromolyn sodium, topical, atopic dermatitis, clinical trial. We identified 19 clinical studies of which 3 used this 4% SCG emulsion formulation, one was a RCT using the change in SCORAD score. We were given access to two further unpublished RCTs, with this measure. The RCTs included 490 subjects (mean age 5.3 years). Each RCT was multicentre of 12 weeks duration, comparing 4% SCG emulsion with the vehicle in which the SCG was dissolved. Using study as the unit and the fixed effect model, the mean difference (95% CI) in the change in SCORAD score was −2.82 (−5.36; −0.29), p = 0.03. Using centre as the unit, and the fixed effect model, the mean difference (95% CI) in the change in SCORAD score was −2.82 (−5.82; −0.46), p = 0.02. These results support the efficacy of this new topical treatment in children with atopic dermatitis.

A randomised, controlled trial of a 4% cutaneous emulsion of sodium cromoglicate in treatment of atopic dermatitis in children

ABSTRACT Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease. Sodium cromoglicate (SCG) is a chromone with anti-inflammatory, anti-itch and anti-allergic activity. This trial is a 12-week comparison (RCT) of a 4% SCG cutaneous emulsion with its vehicle in AD. Materials and methods: 208 children aged 2–12 years participated, 104 in each group. The primary endpoint was change in SCORAD score. Secondary endpoints included SASSAD score, topical steroid usage and global assessments. Results: SCORAD was reduced by 28% (SCG group) and by 19% (vehicle): difference was statistically significant (p = 0.03) after 8 weeks and nearly significant (p = 0.09) after 12. A similar result occurred in SASSAD (p = 0.001 at 8 weeks). In subjects without major protocol deviations (SCG-64, vehicle-63), difference in SCORAD remained significant at 12 weeks (p = 0.04). Weight of topical steroids reduced in both groups: −0.60 ± 1.3 g/day (35%), SCG and −0.05 ± 1.1 g/day vehicle (p = 0.04). Treatment success, defined as investigator global opinion graded very or moderately effective, was significantly more frequent in SCG group (p = 0.025). Application site discomfort reported by 12.5% of subjects in SCG group and 16.5% in vehicle group. Conclusions: SCG 4% cutaneous emulsion provides an effective, well-tolerated, steroid-sparing treatment for AD in children.

The role of the mast cell in asthma

Sirs The May 2003 issue of Clinical & Experimental Allergy contains a review on ‘New insights into the role of the mast cell in asthma’ by C E Brightling and colleagues [1]. I was surprised to read in what is otherwise an excellent review, that ‘About 20–30% of adult asthmatics respond to cromones’. The reference supporting this statement [2] is another review on the role of mast cells in inflammation. In this latter review, however, no supporting reference is provided for the similar statement, ‘Only 20–30% of adult asthmatic patients appear to respond well to drugs in this class’. From where is this figure for responsive patients derived? The first chromone to be developed for the treatment of asthma, sodium cromoglycate, was developed at a time when double-blind, placebo-controlled trials were becoming the norm and in order to obtain a marketing licence, it was necessary to provide clear evidence of efficacy and safety to the then Dunlop Committee. It is extremely doubtful if evidence of efficacy could be obtained if the response rate was only 20–30%. Both mast cell reviews cite the first placebo-controlled, double-blind trial conducted with inhaled sodium cromoglycate [3], which was unique in that it was one of the first clinical trials to use a sequential analysis. Such an approach requires a single end-point and in this case it was the clinical response to treatment as judged by the physician. The trial was conducted in adult patients with severe asthma, all of whom required oral corticosteroids for treatment. The first analysis was conducted after 10 patients had completed the trial and it was found that all 10 had responded to treatment with sodium cromoglycate and not to placebo. Perhaps, if the authors of the mast cell reviews had re-read the article they cited, a small doubt might have arisen as to the accuracy of the figure for responsiveness quoted later in the paragraph. A large number of trials followed this original trial and I will refer to four that looked at clinical response to sodium cromoglycate in adult asthmatics. Two were planned, organized and conducted by independent bodies, the Medical Research Council in the UK [4], and the American Academy of Allergy in the USA [5]. Both were placebo-controlled and conducted as double-blind trials. In the UK study, the end-point was failure of test treatment. After 2 months of treatment, the percentage of responders, that is the percentage of patients considered to be satisfactorily controlled, was 73% for the combination of sodium cromoglycate and isoprenaline, 62% for sodium cromoglycate alone, 31% for isoprenaline alone and 19% for placebo. For patients treated with sodium cromoglycate alone, FEV1 had increased from 55.4% of predicted normal to 72.6% of predicted normal at 1 year. The US trial was to a 4-week treatment, double-blind, crossover design comparing sodium cromoglycate alone with placebo. Two hundred and fifty-two adult asthmatic patients completed the trial. The physicians conducting the trial considered that 72.4% of patients were ‘Very much better’ or ‘Slightly better’ at the end of the sodium cromoglycate treatment. The figure for the placebo treatment was 31%. The other two trials have specifically defined response to treatment as one of the end-points. The trial by Patricia Diaz et al. [6], defined response on the basis of improvement in diary-card symptom scores. Fourteen patients (74%) treated with sodium cromoglycate were classed as responders compared to 35% treated with placebo. Bronchoalveolar lavage was carried out on these patients before and after treatment and in the context of inflammation all the patients responding to sodium cromoglycate showed a reduction in mucus eosinophils (P5 0.005) in the lavage fluid. This did not occur in the non-responders to sodium cromoglycate and in the placebo group. If the number of patients in this trial are too small to assess response and non-response to treatment, the final trial I will cite is one in which sodium cromoglycate was compared to one of the oral anti-leukotriene drugs, zafirlukast, and both were compared to placebo [7]. This is also of interest as the producers of the latest British Guidelines on Asthma Management [8] have decided to replace the chromones with oral anti-leukotrienes. This latter trial included 287 patients with over 90 on each treatment. All were adult asthmatics. Response to treatment was defined by both diary-card and pulmonary function criteria. Some might consider the dosage of sodium cromoglycate used in this trial of 8mg/day too low for an adequate response. Nevertheless, the percentage of patients defined as responders to the three treatments was 70% for zafirlukast, 74% for sodium cromoglycate and 43% for placebo. I have restricted my examples to sodium cromoglycate as this is still the most widely used of the chromones. However, in the overview analysis of nedocromil sodium I published together with Michael Stevens of all placebocontrolled, double-blind trials conducted up to that date with that chromone, the percentage of patients who found the test treatment to be very or moderately effective in trials where nedocromil sodium was added to existing treatment was 54% for nedocromil sodium and 35% for placebo [9]. The two chromones, sodium cromoglycate and nedocromil sodium are licensed for the treatment of asthma, in both adults and children, in most countries of the world. It is almost impossible that such licenses would have been given if the response rate in adult patients was as low as 20–30%. This is in effect stating that the treatment is no better than a placebo. However, when such a figure gets into the scientific literature, it tends to be perpetuated and this already appears to be happening. It should either be corrected or evidence should be provided to support it. It is ironic that this should occur in reviews about mast cells. It is doubtful if the importance of the mast cell in allergic inflammation would have been recognized were it not for all the work conducted showing how the chromones can modulate the effect of this cell in disease. Some years ago I had the privilege of editing, together with the Clin Exp Allergy 2003; 33:1164–1165

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

In their State-of-the-Art Review, ‘The mast cell and allergic diseases: role in pathogenesis and implications for therapy’ [1], the authors state ‘Unfortunately chromones are generally regarded as weak mast cell ‘stabilizers’ and display rapid tachyphylaxis resulting in their poor clinical efficacy.’ They provide no references to support these assertions which can be challenged. The use of term ‘weak’ must be based on the degree to which the chromones, sodium cromoglicate (SCG) and nedocromil sodium (NS), inhibit the release of inflammatory mediators from in vitro cell models. The degree of inhibition is dependent on the type of mast cell used, the animal species from which they are derived, the severity and type of challenge used and the dose of the drug used. In most model systems it is the inhibition of the release of histamine that is used as the outcome measure. In their classic experiments using antigen challenge in passively sensitized human chopped lung, Sheard and Blair [2], showed that the inhibition of SRS-A (leukotriene) release, as a percentage of the total available, was greater than the inhibition of histamine release. Leung et al. [3], measuring histamine release from human pulmonary mast cells, obtained either by bronchoalveolar lavage, or by enzymatic dissociation of lung tissue, reported that both compounds inhibited release of histamine, but were significantly more active against the lavage cells than against the dispersed lung cells. In an earlier experiment from the same unit with SCG, Flint et al. [4] commented, ‘DSCG is a potent inhibitor of histamine release from human airway mast cells. These cells lying superficially within the airways would have the greatest exposure to inhaled DSCG in vivo’. It is usually stated that the chromones have no protective effect on skin mast cells. However, this is based on inhibition of histamine release being the outcome measure and anti-IgE the challenge, Walsh [5], using challenge with ultraviolet B irradiation and release of TNF-a from skin mast cells as the outcome measure showed SCG to be a potent inhibitor of the release of this mediator. Tachyphylaxis has been reported in some models, but this has been in isolated mast cell, or tissue cultures with inhibition of histamine release as the end-point. The results have not been consistent, again depending on the type of mast cell being used in the experiment. Okayama et al. [6], using anti-IgE as the challenge showed that both SCG and NS inhibit histamine release from lung, tonsillar, adenoidal and intestinal mast cells. Both compounds showed tachyphylaxis in lung and tonsillar mast cells but not in intestinal mast cells. Bissonnette et al. [7] showed that both modulated the release of TNF-a from intestinal mast cells and no tachyphylaxis was observed. While these models can help in our understanding of disease processes and how drugs may influence them, they are of no value in determining whether particular drugs are effective in clinical usage. Only clinical trials can do that. If tachyphylaxis was a factor in clinical use one would expect as treatment continued that efficacy would diminish. The first long-term study with inhaled SCG in adult asthma was conducted by the Medical Research Council at the Brompton Hospital in London and the Northern General Hospital in Edinburgh [8, 9]. At the end of 12 months treatment, between 62% and 73% of adult asthmatic patients, treated with inhaled SCG remained adequately controlled. In a similar trial conducted in children with severe perennial asthma conducted at the Department of Paediatrics at the Institute of Diseases of the Chest in London [10], at the end of 12 months treatment 71% of the SCG treated patients remained well controlled while 76% of the control group had been withdrawn because of inadequate control of symptoms. The children successfully treated with SCG during the first year continued treatment and were followed up for 3–5 years [11]. At the end of that time, 63% of children remained well. Morrison-Smith also conducted a trial in severe asthmatic children who needed oral corticosteroids as part of their treatment. After a 10-year follow-up he reported ‘It proved possible gradually to reduce the daily steroid dosage, sometimes to complete withdrawal as was seen in the case of 44 severe asthmatic children who participated in this trial. Today, 10 years later, about 50% are still regularly using DSCG as their only treatment’ [12]. Finally it might be thought that the effects of SCG may not be mast cell related. Two placebo-controlled trials of oral SCG in systemic mastocytosis [13, 14] demonstrate clinically and statistically significant symptom control. Businco et al. treated a 5-year old child with systemic Clinical and Experimental Allergy, 38, 1063–1065 doi: 10.1111/j.1365-2222.2008.03000.x

Immunosuppressant drugs in the treatment of allergic eye disease: do they have potential usage?

The conjunctivae of the eye are exposed to the same wide spectrum of airborne allergens as is the nasal and bronchial mucosa, and also exhibit the same inflammatory allergic responses as these other body surfaces. Immediate and late responses to allergens and delayed hypersensitivity reactions have all been described with the involvement of mast cells, eosinophils, neutrophils, macrophages and T lymphocytes and the numerous mediators released by these cells. The inflammatory conditions that result from these reactions are classified as acute allergic conjunctivitis, seasonal and perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis [1, 2]. Acute, seasonal and perennial allergic conjunctivitis are relatively mild conditions, can occur at any age, and are usually caused by exposure to allergens of plant or animal origin such as grass or tree pollens and house dust mite. The predominant inflammatory cells are mast cells and eosinophils. Vernal keratoconjunctivitis and atopic keratoconjunctivitis are, as the names imply, more severe inflammatory conditions involving the deeper layers of the eye. Vernal keratoconjunctivitis usually presents in boys less than 10 years of age. The symptoms are severe and distressing, intense itching, photophobia, blepharospasm and the production of thick tenacious mucus making it difficult to open the eyes in the mornings. The condition is characterized by subepithelial accumulations of lymphoid tissue forming papillary hypertrophic swellings – ‘cobblestones’. There is also infiltration with eosinophils, mast cells, macrophages and lymphocytes suggesting that both mast cell-IgE-and lymphocyte-mediated reactions are involved. Corneal erosion with plaques of mucus and fibrin preventing re-formation of the epithelium can occur and the resultant scarring is sight threatening. Atopic keratoconjunctivitis has a similar profile of inflammation to the vernal type but primarily affects young adults. Corneal ulceration and scarring can occur as can the development of keratoconus, which may require the patient to wear contact lenses to correct sight. Giant papillary conjunctivitis occurs in eyes in which the conjunctival surface is in contact with foreign material such as contact lenses. Clinically it has similar features to vernal keratoconjunctivitis. The treatment of acute allergic, seasonal allergic and perennial allergic conjunctivitis consists of avoidance of the responsible allergen where possible and the application of antihistamine and anti-inflammatory eyedrops. Antihistamine eyedrops are effective in relieving the itching, oedema and hyperaemia associated with immediate hypersensitivity responses. For more prolonged use, eyedrops containing one of the chromones, sodium cromoglycate or nedocromil sodium, have proven efficacy and safety. In cases of vernal and atopic keratoconjunctivitis, although the chromones can be of benefit in both, it is usually necessary to resort to prolonged treatment with topical corticosteroids. However, long-term topical corticosteroids, as in other clinical situations can result in serious adverse events. Ocular hypertension or glaucoma can affect up to 20% of patients and longer administration can result in cataracts plus the possibility of enhancing infection, in particular herpes simplex keratitis. Although topical corticosteroids are nearly always needed to treat vernal and atopic keratoconjunctivitis, the amount used and the length of treatment can often be reduced by the concomitant use of topical chromones. It would therefore be a major advance if an alternative antiinflammatory agent to corticosteroids became available, particularly if it had equivalent efficacy and without the long-term side-effects. In this issue of the journal, Sengoku et al. [3] from the Medicinal Biology Research Laboratories of Fujisawa Pharmaceutical Co. Ltd. in Japan report on a series of animal experiments in models of allergic eye disease using the immunosuppressant drug tacrolimus hydrate, also known as FK506. Tacrolimus hydrate is a macrolide extracted from the soil bacterium Streptomyces tsukubaensis [4]. It was developed originally as an immunosuppressant and is used worldwide to prevent liver and kidney allograft rejection. More recently, it has been approved in a number of countries as a topical skin ointment for the treatment of moderate to severe atopic dermatitis in adults. Sengoku et al. [3] report the effects of tacrolimus in animal models of late and delayed hypersensitivity reactions in the eye. A late response in rats and guinea pigs was induced by the topical application of egg albumin solution 2 weeks after the animals had been sensitized by intra-peritoneal injection of egg. Delayed responses were induced in rats, guinea pigs and rabbits by the injection of purified protein derivative into the palpebral conjunctivae 2 weeks after sensitization with subcutaneous injections of complete Freund’s adjuvant. In the case of late responses, the conjunctivae were examined microscopically 24 h after challenge in the case of the rat and 6 h after challenge in guinea pigs. Delayed responses in the rat and guinea pig were evaluated by measuring the amount of Evans Blue dye leaking into the palpebral conjunctiva, 20 h after challenge. Delayed responses in the rabbit were evaluated by direct examination of the eyes in the live animal, 24 h after challenge. Clin Exp Allergy 2003; 33:1479–1480

Carl Prausnitz Giles – family doctor and father of reagin detection

AbstractDr. Carl Prausnitz Giles was born in Hamburg, Germany in 1876, the son of Otto Prausnitz, a Physician in the army reserve of the King of Prussia and Edith Giles, daughter of George and Elizabeth Giles of Bonchurch, Isle of Wight, United Kingdom. Carl qualified in Medicine at the Universities of Leipzig, Kiel and Breslau. He began work at the Hamburg Hygiene Institute, undertaking diagnostic work on cholera, plague, typhoid, diphtheria and tuberculosis. Carl frequently visited his mother’s home in Bonchurch and became proficient in both German and English and obtained British medical qualifications, MRCS. LRCP. The key work, for which he is mainly remembered, was the discovery of the principle responsible for the supersensitivity of his co-worker, Küstner, to cooked fish. In a classic paper published in 1921, he showed this could be transferred to non-sensitive individuals. He called it reagin, eventually shown to be IgE antibody. The test demonstrating its existence, the Prausnitz-Küstner reaction, was used for many years to demonstrate allergy in patients. In 1926, Prausnitz was appointed Professor and Director of the Institute of Hygiene in Breslau. Due to his Jewish antecedents, in 1934 he was compulsorily retired from his Chair in Breslau and moved his family to England. In 1935 he moved to Bonchurch. At the age of 60 years he embarked on a career in General Practice in partnership with a childhood friend, Dr. Bruce Williamson. He took his mother’s maiden name and became Dr. CP Giles of Ventnor, Isle of Wight. UK.

Long-term use of a 4% sodium cromoglicate cutaneous emulsion in the treatment of moderate to severe atopic dermatitis in children

Abstract Introduction: Sodium cromoglicate (SCG), a chromone with anti-inflammatory, anti-itch and anti-allergic properties. We report a long-term study of a 4% aqueous solution of SCG in children with moderate to severe atopic dermatitis (AD). Materials and methods: Children aged 1 to 12 years with AD were entered into a 12-week randomised clinical trial (RCT), followed by 12 months open treatment with known 4% SCG emulsion (Altocrom®). Primary endpoint was change in SCORAD score. Secondary endpoints included symptom severity, Quality of Life, concomitant treatment usage, global assessments. Results: One hundred and seventy-seven subjects entered, 118 treated with 4% SCG emulsion and 59 with vehicle: 128 completed 12 months in open study. SCORAD score reduced during RCT by −15.3 (−33%) on 4% SCG emulsion and −18.0 (−39%) on vehicle: p = 0.2331. After 12 months reduction was 56%. No secondary endpoint showed differences between treatments during RCT. Thirty-two subjects reported treatment related events during RCT and open trial. Eleven (7%) reported application site discomfort. Most were reported as mild and most resolved without intervention and the study drug was stopped in one case only. Conclusions: SCG 4% cutaneous emulsion was well tolerated in children treated for 15 months.