Topical Cromolyn Research Articles

Mast Cells Are Key Mediators of Cathelicidin-Initiated Skin Inflammation in Rosacea

Rosacea is a chronic inflammatory skin disease whose pathophysiological mechanism is still unclear. However, it is known that mast cell (MC) numbers is increased in the dermis of rosacea patients. MC proteases not only recruit other immune cells, which amplify the inflammatory response, but also cause vasodilation and angiogenesis. MCs are also one of the primary sources of cathelicidin LL-37 (Cath LL-37), an antimicrobial peptide that has been shown to be an enabler of rosacea pathogenesis. Here, we demonstrate that MCs are key mediators of cathelicidin initiated skin inflammation. Following Cath LL-37 injection into the dermis, MC deficient B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh) mice did not develop rosacea-like features. Conversely, chymase (p<0.001), tryptase and Mmp9 (p<0.01) mRNA levels were significantly higher in C57BL/6 Wild Type (WT) mice. Treating WT mice with a MC stabilizer significantly decreased the expressions of Mmp9 and Cxcl2 (p<0.01). Our data was confirmed on Erythematotelangiectatic rosacea subjects that showed a decrease in MMP activity (p<0.05), after eight weeks of topical cromolyn treatment.We conclude that MCs play a central role in the development of inflammation subsequent to Cath LL-37 activation and that down regulation of activated MCs may be a therapy for rosacea treatment.

Cromolyn Sodium for Insulin-Induced Lipoatrophy: Old Drug, New Use

Local insulin-induced lipoatrophy, an immune-mediated loss of subcutaneous adipose tissue at insulin administration sites, is now a rare complication of insulin therapy in patients with diabetes. Lipoatrophy incidence, previously noted in 10–55% of patients using animal-derived insulins (1), declined considerably with the advent of and improved purity of modern insulins. Yet, it continues to be reported with insulin analogs (2,3) and poses a clinical challenge owing to erratic insulin absorption at affected areas and distressing cosmetic issues. We previously demonstrated increased degranulating tryptase/chymase-positive mast cells in biopsies from insulin-induced lipoatrophic sites and reported that topical cromolyn sodium (prepared with 4% cromolyn sodium in petrolatum solvent for topical administration twice daily to affected areas) was efficacious therapy in a small series (4). Since this report, we were contacted by 34 health care providers, caregivers, and patients worldwide, to whom we administered surveys to …

Efficacy of topical cromolyn sodium 4% on pruritus in uremic nephrogenic patients: A randomized double-blind study in 60 patients

Chronic kidney disease (CKD)-associated pruritus is a significant clinical symptom affecting more than 50% of patients on hemodialysis. The availability of effective therapeutic options for management of CKD-associated pruritus remains a treatment challenge. The aim of this study was to compare cromolyn sodium cream 4% with placebo for the treatment of renal pruritus. A randomized, double-blind, prospective, 4-week study was designed. 60 patients with ESRD in our dialysis ward were randomly allocated to cromolyn sodium cream 4% or placebo. All of them completed the study period and their pruritus levels were evaluated 5 times (before the start of the study and at the end of each week for 4 weeks) using a Visual Analogue Scale (VAS). The average pruritus score before administration of the drug in cromolyn sodium 4% and placebo group had been 2.5 ± 1.1 and 2.7 ± 1.3, respectively. In the cromolyn sodium 4% group the average score of pruritus gradually reduced to 0.3 ± 1.3 and in the placebo group it gradually decreased to 1.3 ± 1.4 at the end of Week 4. Method of t-test repeat analytical measurement indicated that there is no significant difference between reduction of pruritus in cromolyn 4% and placebo groups in the first and second week of the study, but in third and fourth week there were significant differences in reducing pruritus in favor of cromolyn sodium 4% (p < 0.04). According to our study cromolyn sodium cream 4% was more effective than placebo in reducing pruritus in uremic patients. We suggest to our colleagues to consider this treatment when facing a patient suffering from this symptom.

A double-masked study to compare the efficacy and safety of topical cromolyn for the treatment of allergic conjunctivitis

To compare the efficacy and safety of topical cromolyn between with and without preservative for the treatment of allergic conjunctivitis. A double-masked study was performed in patients with allergic conjunctivitis. Each cromolyn sodium 2% ophthalmic solution with or without 0.01% benzalkonium chloride (BAK) was randomized to apply on either eye. The efficacy and safety were evaluated every other week by a questionnaire about ocular itching, redness and foreign body sensation, and objective scores of conjunctival redness, chemosis, cornea erosion and discharge using slit-lamp biomicroscopy. An overall response was also rated by physician's impression. A total of 37 subjects were enrolled in this study but only 33 completed the study. All of subjective questionnaire scores showed a significant improvement after treatment in both groups. Objective score of redness significantly decreased after treatment in either groups but not chemisos or discharge. After 4-week treatment, corneal erosion diminished significantly in the group without preservative but not in the group with 0.01% BAK. There was no significant difference between with and without 0.01% BAK groups in each subjective or objective score. No adverse effect related with medication was observed. Cromolyn 2 % ophthalmic solution was effective and safe to treat allergic conjunctivitis. A short-term use of cromolyn 2 % ophthalmic solution with 0.01% BAK would not cause any significant toxicity in patients with allergic conjunctivitis. Preservative-free cromolyn may be beneficial to the compromised eyes or eyes required of long-term medication.

Human Insulin Analog–Induced Lipoatrophy

To characterize the pathophysiology of recombinant human insulin-induced lipoatrophy. We performed immunologic laboratory evaluation and skin testing for different insulin analogs and diluents in patients with type 1 diabetes and severe insulin-induced local lipoatrophy. Subcutaneous adipose tissue biopsies of areas of acute (7 days) and chronic insulin administration were examined. Topical sodium cromolyn was applied twice a day to atrophic areas and prophylactically to new sites of insulin administration. Subcutaneous adipose biopsies showed an elevated population of tryptase-positive, chymase-positive degranulated mast cells. Of five patients treated with topical sodium cromolyn, none had new lipoatrophic sites and four showed improvements in old lesions. Tryptase-positive/chymase-postitive mast cells, known to be sensitive to sodium cromolyn, may contribute to the destructive immune process mediated in response to exogenous insulin. Mast cell stabilizing therapy with topical cromolyn may reverse early and prevent new lipoatrophic lesions.

Treatment of eosinophilic esophagitis in children

Eosinophilic esophagitis (EE) is an increasingly recognized disease of the esophagus with distinct clinicopathologic features. Adult and pediatric patients experience upper intestinal symptoms including food impaction, vomiting, abdominal pain, or dysphagia. Histopathologic analysis of the distal and proximal esophageal mucosa demonstrates dense eosinophilic infiltration despite proton pump inhibition. Few studies document the long-term outcomes of EE but current evidence suggests that EE is a chronic condition that can sometimes lead to esophageal strictures. Although the incidence of this complication is not yet known, it has sparked significant interest in defining safe, effective treatments. Once a diagnosis of EE is made, patients should seek the consultation of the allergist in an effort to identify possible food sensitivities. This is particularly important because the etiologic agent(s) that drive the eosinophilia are likely different for each patient. If the allergic evaluation identifies a specific food, this food should be strictly avoided as a first-line treatment. If a food is not identified, an elemental formula should be used to induce a remission. If an elemental diet cannot be used, topical steroids are effective in inducing a remission. The side effects associated with long-term steroid administration limit their use as a maintenance medication. Given the lack of prognostic data, the use of systemic corticosteroids should be reserved for severe cases when dietary elimination or topical steroids are ineffective. Most importantly, patients should remain under the care of a physician so that long-term outcomes can be identified. To date, diet restriction has been identified as the only effective maintenance treatment, but montelukast and topical cromolyn may also offer benefit. Anti-interleukin-5 antibody represents an emerging form of targeted therapy.

Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules.

Systemic hypoxia, produced by lowering inspired Po2, induces a rapid inflammation in several microcirculations, including cremaster muscle. Mast cell activation is a necessary element of this response. Selective reduction of cremaster microvascular Po2 (PmO2) with normal systemic arterial Po2 (PaO2; cremaster hypoxia/systemic normoxia), however, does not elicit increased leukocyte-endothelial adherence (LEA) in cremaster venules. This could be due to a short time of leukocyte exposure to the hypoxic cremaster environment. Conversely, LEA increases when PaO2 is lowered, while cremaster PmO2 remains high (cremaster normoxia/systemic hypoxia). An alternative explanation of these results is that a mediator released from a central site during systemic hypoxia initiates the inflammatory cascade. We hypothesized that if this is the case, cremaster mast cells would be activated during cremaster normoxia/systemic hypoxia, but not during cremaster hypoxia/systemic normoxia. The microcirculation of rat cremaster muscles was visualized by using intravital microscopy. Cremaster PmO2 was measured with a phosphorescence quenching method. Cremaster hypoxia/systemic normoxia (PmO2 7 +/- 1 Torr, PaO2 87 +/- 2 Torr) did not increase LEA; however, topical application of the mast cell activator compound 48/80 under these conditions did increase LEA. The effect of compound 48/80 on LEA was blocked by topical cromolyn, a mast cell stabilizer. LEA increased during cremaster normoxia/systemic hypoxia, (PmO2 64 +/- 5 Torr, PaO2 33 +/- 2 Torr); this increase was blocked by topical cromolyn. The results suggest that mast cell stimulation occurs only when PaO2 is reduced, independent of cremaster PmO2, and support the idea of a mediator that is released during systemic hypoxia and initiates the inflammatory cascade.

Poor sleep and daytime somnolence in allergic rhinitis: significance of nasal congestion.

Patients with allergic rhinitis frequently present with symptoms of nasal congestion, runny nose, sneezing, daytime somnolence and fatigue associated with decreased cognitive performance and impaired quality of life. Recent research has suggested that daytime somnolence in allergic rhinitis can be attributed to chronic inflammation of the nasal mucosa leading to nasal congestion and obstructed nasal passageways resulting in disturbed sleep. Treating daytime somnolence due to allergic rhinitis requires a reduction in obstruction caused by nasal congestion. Currently available therapy for allergic rhinitis includes topical corticosteroids, sedating and nonsedating antihistamines, topical cromolyn sodium (sodium cromoglycate), decongestants, immunotherapy and topical ipratropium bromide. The effectiveness of antihistamines in patients with allergic rhinitis has long been established. However, results of placebo-controlled trials investigating the effects of azelastine on sleep and daytime somnolence have produced conflicting results. Sleep improved with azelastine therapy, but there was a lack of evidence that azelastine significantly affected daytime sleepiness, sleep severity and nasal congestion. Sedating antihistamines exacerbate daytime somnolence and should be avoided in patients with allergic rhinitis. In a separate study, desloratadine failed to benefit sleep, but did not worsen daytime somnolence. Topical nasal cromolyn sodium is inconvenient to use and is unlikely to have a major effect on nasal congestion. Decongestants do decrease nasal congestion but the effect this has on sleep has not been adequately studied. Recent research has shown that topical corticosteroids are an effective treatment for alleviating nasal congestion secondary to allergic rhinitis. However, few studies have assessed the effect of topical corticosteroids on daytime fatigue and sleep. In 20 patients with allergic rhinitis and symptoms of daytime sleepiness, flunisolide significantly improved sleep quality and congestion but daytime sleepiness was not significantly improved. A similar study with fluticasone propionate showed improvement in nasal congestion and sleep but there was no significant change in objective sleep measurements recorded on polysomnography. Further research involving objective measures of sleep quality is necessary to determine the efficacy of medications in the treatment of allergic rhinitis associated with fatigue and daytime somnolence.

Clinical features and treatment of peristomal pyoderma gangrenosum.

Peristomal pyoderma gangrenosum (PPG), an unusual variant of pyoderma gangrenosum, has been reported almost exclusively in patients with inflammatory bowel disease (IBD) and is frequently misdiagnosed. To better characterize the clinical manifestations, diagnosis, and management of PPG. Retrospective analysis of 7 patients with PPG observed in a university-affiliated community setting between 1988 and December 1999. Clinical and histopathologic features, associated disorders, and microbiologic findings. Two patients had Crohn disease, 2 had ulcerative colitis, and 3 had abdominal cancer. Five patients had at least 1 relapse of PPG after initial healing. Although 3 of 4 patients with IBD had active bowel disease, a parallel course with PPG occurred in only 1 patient. Both patients whose stoma was relocated developed an ulcer at the new site. Effective therapies included topical superpotent corticosteroids; intralesional injection of triamcinolone acetonide at the ulcer margin; topical cromolyn sodium; oral dapsone, prednisone, cyclosporine, mycophenolate mofetil; and intravenous infliximab. Our experiences demonstrate that although PPG has been most often reported in patients with IBD, it may occur in the absence of IBD. Biopsy of the skin lesion is not diagnostic but excludes other causes. Relocation of the stoma may be associated with a new ulceration and should be avoided. Trauma to the skin of a predisposed patient may elicit the pustules or ulcerations associated with pathergy. JAMA. 2000;284:1546-1548.

Mechanisms and comparison of anti-allergic efficacy of topical lodoxamide and cromolyn sodium treatment in vernal keratoconjunctivitis

Purpose: To explore the mechanism of action of topical lodoxamide and cromolyn sodium treatment in vernal keratoconjunctivitis (VKC) and to compare the efficacy of these drugs to each other. Design Single-investigator, masked, randomized, clinical trial. Participants Twenty male and 10 female patients between the ages of 6 and 19 years, who were diagnosed as having active VKC, were enrolled in this study. Interventions The patients were randomly divided into two equal groups (groups A and B). Group A patients received topical lodoxamide ophthalmic solution 0.1% (LOS); topical cromolyn sodium ophthalmic solution 4% (CSO) was prescribed to group B patients in a dose of two drops four times daily. Main outcome measures The eye symptom severity scores and clinical signs of the patients were evaluated both in the pre- and post-treatment periods. In addition to the clinical data, conjunctival impression cytologic specimens were obtained from patients both before and after treatment. Impression cytologic specimens were stained using immunohistochemical methods to detect the percentages of CD4 +, CD8 +, CD45RA +, and CD23 + cells. Statistical analyses were performed within and between groups. Results The percentages of CD4 + and CD23 + cells in tear samples of patients in groups A and B were significantly higher in the pretreatment stage than post-treatment stage. In the post-treatment stage, group A patients had significantly lower CD4 + and CD23 + cell values compared with group B patients. Patient symptom scores and clinical signs were at a significantly lower level after treatment with either LOS or CSO in both groups A and B compared with their pretreatment values. Moreover, group A patients had significantly lower symptom scores and clinical signs than group B patients in the post-treatment stage. Conclusions Clinical superiority of LOS over CSO may be linked to its greater effect on the CD4 + cells, because CD4 + cells plays a pivotal role in the pathogenesis of VKC.

Allergen-Mediated Disease

A nasal corticosteroid is the most effective treatment for allergic rhinitis, but delayed improvement can reduce compliance. Topical vasoconstrictors, cromolyn, and NSAIDs are recommended for allergic conjunctivitis. Some athletes who have exercise-induced or exercise-exacerbated asthma may have a refractory period, which, along with short- and long-term beta-2 agonists, inhaled corticosteroids, and leukotriene antagonists, may be used to manage symptoms. Topical steroids are the main treatment for atopic dermatitis. Drug restrictions by sports governing bodies can limit therapies for competitive athletes.

Topical Sodium Cromoglycate in the Treatment of Moderate-to-Severe Atopic Dermatitis

Unsatisfactory treatment results for severe atopic dermatitis have led to many experimental therapies, including cromolyn sodium in various vehicles at concentrations ranging from 1% to 10%. Results suggest that the vehicle used to deliver the cromolyn is relevant to its effectiveness. To test the efficacy of low concentrations of cromolyn in a water-soluble vehicle in the treatment of moderate-to-severe atopic dermatitis in a double-blind, placebo-controlled study. Twenty-six pediatric patients who had failed to respond to conventional therapy were randomized into 2 treatment groups: patients in group A used the study drug for 1 month (phase I), then received the placebo for 1 month (phase II); and patients in group B used the placebo for 1 month, then received the study drug for 1 month. The study drug was cromolyn sodium inhalation solution mixed into a water-based emollient cream to a final concentration of 0.21%. Upon enrollment and at each follow-up visit, every patient was given a severity score based on extent and severity of skin involvement. At enrollment, there were no significant differences between groups A and B in severity scores, age, sex, race, skin test and/or RAST positivity, eosinophil levels, IgE concentrations, or the presence of concomitant rhinitis or asthma. After the first phase of the study treatment, severity scores had decreased significantly for both groups with a significant difference between group A (cromolyn) and group B (placebo). After crossover, both groups had significantly lower severity scores than at entry into the study. Treatment with topical cromolyn in a hydrophilic emollient vehicle has a significant anti-inflammatory effect on moderate-to-severe atopic dermatitis. We have now incorporated this treatment into our clinical practice.

Topical cromolyn can modify human allergic skin reactions

Topical cromolyn can modify human allergic skin reactions

Atypical Ocular Atopy

Atopic keratoconjunctivitis (AKC) is defined as a chronic keratoconjunctivitis associated with atopic dermatitis, but severe progressive keratoconjunctivitis as a sole manifestation of atopy also may occur. The authors report three patients with a longstanding history of chronic conjunctivitis with bilateral pannus formation. These patients denied any history of major atopy at the time of presentation. All patients were evaluated for collagen vascular disease and for evidence of atopy. Conjunctival biopsy was obtained in each case and was analyzed by light microscopy and by immunohistochemical techniques. Systemic evaluation for collagen vascular disease was negative. Serum IgE levels were elevated in one patient. Conjunctival biopsy suggested atopy in all patients with characteristic histopathologic findings. Referral to an allergist showed wheal and flare reactions to multiple ubiquitous environmental allergens. Two patients then disclosed a history of atopic dermatitis and another confessed a history of asthma. Each patient responded well to environmental control of allergens, topical cromolyn sodium 4%, and systemic antihistamine therapy with subsequent resolution of the chronic conjunctivitis. The corneal complications were managed with pannus resection and postoperative mitomycin C drops in two patients. These patients suffered from the progressive blinding consequences of a chronic keratoconjunctivitis, which we believe is an atypical form of AKC. In this report, it is suggested that atopy should be considered in some cases of external ocular inflammation, even in the absence of the characteristic findings of systemic atopy. Conjunctival biopsy is a valuable diagnostic tool in such cases.

Cultured Allografts as an Adjunct to the Medical Treatment of Problematic Leg Ulcers

REPORT OF CASES Case 1.— A 33-year-old black woman had a 15-year history of multiple recalcitrant skin ulcers on the lower extremities. The skin biopsy specimen showed typical features of sarcoidosis. Also, pulmonary involvement with lethargy, dyspnea on exertion, bilateral hilar lymphadenopathy, and diffuse interstitial shadowing on chest roentgenogram were present. Her leg ulcers were initially treated with hydroxychloroquine, with temporary healing. Subsequent recurrences of the ulcers were unresponsive to hydroxychloroquine therapy, and systemic corticosteroids were prescribed. The ulcers did not respond either to therapy with intralesional triamcinolone or to increasing doses of oral prednisone up to 60 mg/d. Her steroid therapy was complicated by hypertension and insulin-dependent diabetes. Because of recurring ulcerations on her legs, hydroxychloroquine (800 mg/d) was added to the patient's steroid regimen. The ulcers healed temporarily for 2 months but recurred when the antimalarial dosage was reduced to 400 mg/d. A trial of topical cromolyn sodium

Predictive value of airway reactivity

DISCUSSION Question. We have all had patients with severe allergic rhinitis and mild asthma, and we have brought their allergic rhinitis under control with an antihistamine or a topical steroid or topical cromolyn. The asthma also seems to become much better; in fact, it will sometimes resolve clinically. Can you comment on the role of antihistamines in treating allergic rhinitis and how controlling the allergic rhinitis seems to reduce either bronchial hyperreactivity or at least the stimulus to bronchospasm? Dr. Rafferty. I do not know of any studies looking at changes in bronchial hyperreactivity per se, but stimulation of the nasal mucosa with histamine can result in a degree of reflex bronchoconstriction in subjects with asthma. Therefore control of rhinitis may have contributed to a reduction in some asthma symptoms. Question. What are your speculations as to how newer antihistamines may be helpful in asthma, other than their antihistaminic property? Do they have effects on the vasculature, on the smooth muscle, or on other cell types, in the early phase as well as in the late phase? Dr. Rafferty. In addition to its antihistaminic effect, azelastine is reported to antagonize leukotrienes. Because these are potent bronchoconstrictors that are released during the immediate allergic reaction, their blockade could certainly contribute to a reduction in the bronchoconstrictor response. Similarly, if cetirizine is able to inhibit inflammatory cell migration, this is likely to be of great relevance. If it is possible to block either the migration of inflammatory cells in the late response or the subsequent secondary activation, then both these effects are likely to reduce the severity of the late response.

Topical cromolyn (disodium cromoglycate) solution in the treatment of young children with atopic dermatitis

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

Plasmapheresis Treatment in Patients with Severe Atopic Keratoconjunctivitis

A 19-year-old woman with hyperimmunoglobulinemia E (the hyper-IgE syndrome [HIE]) and a 62-year-old man with atopic dermatitis experienced dramatic improvement in their chronic ocular symptoms and signs of atopic keratoconjunctivitis after plasmapheresis was instituted. Both patients had previously received topical and oral corticosteroids as well as topical cromolyn sodium without significant beneficial effect. The authors recommend a trial of plasmapheresis in selected patients with recalcitrant and debilitating atopic keratoconjunctivitis when standard therapy proves unsuccessful.

Evaluation of Topical Cromolyn Sodium in the Treatment of Vernal Keratoconjunctivitis

A randomized, double-masked, placebo-controlled multicenter study was conducted for 6 weeks in 12 centers to evaluate the efficacy and safety of Cromolyn sodium 4% ophthalmic solution (Opticrom) for the treatment of active bilateral vernal conjunctivitis. Objective clinical signs were graded weekly by an ophthalmologist while patients kept a daily record of the severity of their symptoms. Sixty-five patients completed the study; 35 received Cromolyn sodium and 30 were treated with a matching placebo (the drug vehicle). Statistically significant differences in favor of Cromolyn sodium treatment were found for conjunctival injection, timbal injection, timbal edema, tearing, and symptoms summary score. There were few side effects (usually mild stinging and burning which did not require drug stoppage). Only one patient required drug discontinuation for possible drug- or vehicle-related side effects. Cromolyn sodium was found to be significantly more effective than placebo in treating the signs and symptoms of vernal keratoconjunctivitis (VKC). When results were stratified in terms of the atopic status of the patient, it was clear that the allergic patients responded better to Cromolyn sodium than did those in whom allergic (IgE-mediated) factors appeared unimportant in the disease process.

Rhinitis in the athlete

Trauma is the most common problem involving the nose in sports and athletic events. Injury may lead to “vasomotor syndrome” and chronic rhinitis. Nasal and sinus obstruction may cause additional discomfort. Exposure to irritants, particularly solvents, cleaning solutions, paints, and varnishes as well as air pollutants exacerbates vasomotor rhinitis. Allergic rhinitis is another major problem of atopic athletes. It may be caused by exposure to pollens, molds, dust, or animal danders. Treatment is aimed at reducing the exposure to etiologic factors as well as pharmacologic management. Antihistamines, topical cromolyn, and topical steroids may be used to control rhinitis without violating “antidoping” regulations.