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A randomized, double-blinded, placebo-controlled study of the use of viscous oral cromolyn sodium for the treatment of eosinophilic esophagitis.
Lieberman, JA, Zhang, J, Whitworth, J, Cavender, C
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2018;(5):527-531
Abstract
BACKGROUND There is a need for effective, nonsteroid pharmacologic therapies for eosinophilic esophagitis (EoE). Cromolyn sodium offers an option because mast cells have been implicated in the symptomatology of EoE and cromolyn has been shown to have some anti-eosinophilic properties. OBJECTIVE To evaluate the efficacy of cromolyn in decreasing esophageal eosinophilia in patients with EoE. Secondary outcomes included symptom improvement and adverse effects. METHODS We conducted a randomized, double-blinded, placebo-controlled trial of viscous oral cromolyn for EoE in pediatric patients. Subjects were randomized to 100 mg (2-11 years of age) or 200 mg (12-17 years of age) of cromolyn or placebo 4 times daily. The medications were mixed with powdered sugar at home to make them viscous. RESULTS Sixteen subjects (50% boys, median age 11.4 years) were enrolled. Nine were randomized to cromolyn and 7 were randomized to placebo. Cromolyn decreased the peak eosinophil count from 62.1 to 57.3 eosinophils per high-powered field (P = .78) and placebo decreased the peak eosinophil count from 87.0 to 71.3 eosinophils per high-powered field (P = .62) One subject randomized to cromolyn and none in the placebo arm had complete resolution of eosinophilia. Cromolyn decreased symptoms scores from a mean baseline score of 37.8 to a mean post-therapy score of 17.5, which was a 54% decrease (P = .04). Placebo decreased the symptom scores from a baseline score of 32.2 to a post-therapy score of 23.3, which was a 28% decrease (P = .05). CONCLUSION Cromolyn, when mixed into a viscous preparation, did not significantly decrease esophageal eosinophilia. However, it did decrease symptom scores (although not significantly more than placebo) and led to complete resolution in 1 subject.
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Cromolyn sodium for the prevention of chronic lung disease in preterm infants.
Ng, G, Ohlsson, A
The Cochrane database of systematic reviews. 2017;(1):CD003059
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BACKGROUND This is an update of a review last published by Cochrane in June 2012 entitled "Cromolyn sodium for the prevention of chronic lung disease in preterm infants", which included two studies. This 2016 update identified no further studies.Chronic lung disease (CLD) frequently occurs in preterm infants and has a multifactorial aetiology including inflammation. Cromolyn sodium is a mast cell stabiliser that inhibits neutrophil activation and neutrophil chemotaxis and therefore may have a role in the prevention of CLD. OBJECTIVES To determine the effect of prophylactic administration of cromolyn sodium on the incidence of CLD at 28 days or 36 weeks' postmenstrual age (PMA), mortality, or the combined outcome of mortality and CLD at 28 days or 36 weeks' PMA in preterm infants. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 4), MEDLINE via PubMed (1966 to 12 May 2016), Embase (1980 to 12 May 2016), and CINAHL (1982 to 12 May 2016). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA We included randomised or quasi-randomised controlled clinical trials involving preterm infants. Initiation of cromolyn sodium administration was during the first two weeks of life. The intervention had to include administration of cromolyn sodium by nebuliser or metered dose inhaler with or without spacer device versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: overall mortality, CLD at 28 days, CLD at 36 weeks' PMA, or the combined outcome mortality and CLD at 28 days. DATA COLLECTION AND ANALYSIS We used the standard method for Cochrane as described in the Cochrane Handbook for Systematic Reviews of Interventions. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous data. The meta-analysis used a fixed-effect model. We examined heterogeneity using the I2 statistic. We assessed the quality of evidence for the main comparison at the outcome level using the GRADE approach. MAIN RESULTS We identified two eligible studies with small numbers of infants enrolled (64 infants). Prophylaxis with cromolyn sodium did not result in a statistically significant effect on the combined outcome of mortality and CLD at 28 days (typical RR 1.05, 95% CI 0.73 to 1.52; typical RD 0.03, 95% CI -0.20 to 0.27; 2 trials, 64 infants; I2 = 0% for both RR and RD); mortality at 28 days (typical RR 1.31, 95% CI 0.52 to 3.29; I2 = 73% typical RD 0.06, 95% CI -0.13 to 0.26; I2 = 87%; 2 trials, 64 infants) (very low quality evidence); CLD at 28 days (typical RR 0.93, 95% CI 0.53 to 1.64; I2 = 40%; typical RD -0.03, 95% CI -0.27 to 0.20; I2 = 38%; 2 trials, 64 infants) or at 36 weeks' PMA (RR 1.25, 95% CI 0.43 to 3.63; RD 0.08, 95% CI -0.29 to 0.44; 1 trial, 26 infants). There was no significant difference in CLD in survivors at 28 days (typical RR 0.97, 95% CI 0.58 to 1.63; typical RD -0.02, 95% CI -0.29 to 0.26; I2 = 0% for both RR and RD; 2 trials, 50 infants) or at 36 weeks' PMA (RR 1.04, 95% CI 0.38 to 2.87; RD 0.02, 95% CI -0.40 to 0.43; 1 trial, 22 infants). Prophylaxis with cromolyn sodium did not show a statistically significant difference in overall neonatal mortality, incidence of air leaks, necrotising enterocolitis, intraventricular haemorrhage, sepsis, and days of mechanical ventilation. There were no adverse effects noted. The quality of evidence according to GRADE was very low for one outcome (mortality to 28 days) and low for all other outcomes. The reasons for downgrading the evidence was due to design (risk of bias in one study), inconsistency between the two studies (high I2 values for mortality at 28 days for both RR and RD), and lack of precision of estimates (small sample sizes). Further research does not seem to be justified. AUTHORS' CONCLUSIONS There is currently no evidence from randomised trials that cromolyn sodium has a role in the prevention of CLD. Cromolyn sodium cannot be recommended for the prevention of CLD in preterm infants.
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Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Elderly Volunteers.
Brazier, D, Perry, R, Keane, J, Barrett, K, Elmaleh, DR
Clinical drug investigation. 2017;(11):1025-1034
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UNLABELLED BACKGROUND AND OBJECTIVES The combination of cromolyn and ibuprofen is being investigated as a treatment for early Alzheimer's disease (AD). This study investigated the pharmacokinetics, safety, and tolerability of cromolyn and ibuprofen co-administration in healthy elderly adult volunteers. METHODS In this open-labeled study, 26 subjects, aged 55-75 years, received co-administration of inhaled cromolyn (single dose 17.1 mg; double dose 34.2 mg total) and oral ibuprofen (single dose 10 mg; double dose 20 mg total). Blood sampling was performed for 6 h after co-administration in all subjects; cerebrospinal fluid (CSF) was collected in three to four subjects per cohort for 4 h following co-administration. Safety parameters, including adverse events (AEs), were monitored throughout the study. RESULTS For cromolyn, the mean (±SD) maximum observed concentration (C max) in plasma was 46.69 ± 32.97 and 96.75 ± 46.22 ng/ml after single- and double-dose inhalation, respectively [time to C max (t max) ~22 min for each; terminal elimination half-life (t ½) ~1.8 h for each]. For ibuprofen, the plasma C max was 1090.98 ± 474.64 ng/ml and 2062.96 ± 655.13 ng/ml after single- and double-dose oral administration, respectively (t max ~1.6-1.8 h; t ½ ~1.9 h for each). For cromolyn, the CSF C max was 0.24 ± 0.08 ng/ml at 3.72 ± 0.70 h after single-dose administration and 0.34 ± 0.17 ng/ml at 3.45 ± 0.95 h after double-dose administration, and for ibuprofen, the CSF C max was 3.94 ± 1.29 ng/ml at 2.55 ± 0.96 h after single-dose administration and 8.93 ± 3.29 ng/ml at 3.15 ± 1.05 h after double-dose administration. Three (12%) subjects reported mild or moderate AEs which were unlikely to be related to study drug. CONCLUSIONS The combination of cromolyn and ibuprofen was safe and well tolerated. The concentrations of cromolyn and ibuprofen observed in the CSF are considered sufficient to titrate the estimated daily amyloid production and the associated inflammatory response in patients with AD.
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A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial.
Birring, SS, Wijsenbeek, MS, Agrawal, S, van den Berg, JWK, Stone, H, Maher, TM, Tutuncu, A, Morice, AH
The Lancet. Respiratory medicine. 2017;(10):806-815
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BACKGROUND Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. METHODS This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. FINDINGS Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. INTERPRETATION This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation. FUNDING Patara Pharma.
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Long-term use of a 4% sodium cromoglicate cutaneous emulsion in the treatment of moderate to severe atopic dermatitis in children.
Edwards, AM, Bibawy, D, Matthews, S, Tongue, N, Arshad, SH, Lødrup Carlsen, K, Øymar, K, Pollock, I, Clifford, R, Thomas, A, et al
The Journal of dermatological treatment. 2015;(6):541-7
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.
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A randomised, controlled trial of a 4% cutaneous emulsion of sodium cromoglicate in treatment of atopic dermatitis in children.
Berth-Jones, J, Pollock, I, Hearn, RM, Lewis-Jones, S, Goodfield, M, Griffiths, CE, Gulati, R, McHenry, P, Abdullah, A, Ott, J, et al
The Journal of dermatological treatment. 2015;(3):291-6
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.
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Efficacy of topical cromolyn sodium 4% on pruritus in uremic nephrogenic patients: a randomized double-blind study in 60 patients.
Feily, A, Dormanesh, B, Ghorbani, AR, Moosavi, Z, Kouchak, M, Cheraghian, B, Mousavi, SS, Mehrabian, A, Ranjbari, N
International journal of clinical pharmacology and therapeutics. 2012;(7):510-3
Abstract
BACKGROUND 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. OBJECTIVE The aim of this study was to compare cromolyn sodium cream 4% with placebo for the treatment of renal pruritus. METHODS 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). RESULTS 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). CONCLUSION 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.
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Cromolyn sodium for the prevention of chronic lung disease in preterm infants.
Ng, G, Ohlsson, A
The Cochrane database of systematic reviews. 2012;(6):CD003059
Abstract
BACKGROUND Chronic lung disease (CLD) frequently occurs in preterm infants and has a multifactorial aetiology including inflammation. Cromolyn sodium is a mast cell stabiliser that inhibits neutrophil activation and neutrophil chemotaxis and may, therefore, have a role in the prevention of CLD. OBJECTIVES To determine the effect of prophylactic administration of cromolyn sodium on the incidence of CLD, mortality or the combined outcome of mortality or CLD at 28 days of life in preterm infants at risk of CLD. SEARCH METHODS The search strategy of the Cochrane Neonatal Review Group was used to identify studies. Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2009), MEDLINE, EMBASE, CINAHL up to and including July 2009, personal files and reference lists of identified trials. For this update the same data bases were searched on 12 April 2012. In addition, on the same date, abstracts from the Pediatric Academic Societies' Annual Meetings (2000 to 2012) were searched on the website PAS2View(TM) as was the Web of Science website using the two previously identified trials as starting points. SELECTION CRITERIA Randomised or quasi-randomised controlled clinical trials involving preterm infants. Initiation of cromolyn sodium administration during the first two weeks of life. The intervention had to include administration of cromolyn sodium by nebuliser or metered dose inhaler with or without spacer device versus placebo or no intervention. Eligible studies had to include at least one of the following outcomes: overall mortality, CLD at 28 days, CLD at 36 weeks' postmenstrual age (PMA), or the combined outcome mortality or CLD at 28 days. DATA COLLECTION AND ANALYSIS The standard method for The Cochrane Collaboration as described in the Cochrane Handbook for Systematic Reviews of Interventions was used. Risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) are reported for dichotomous outcomes and weighted mean difference (WMD) for continuous data. A fixed-effect model was used for meta-analysis. Heterogeneity was examined using the I(2) statistic. MAIN RESULTS Two eligible studies were identified with small numbers of infants enrolled. Prophylaxis with cromolyn sodium did not result in a statistically significant effect on the combined outcome of mortality or CLD at 28 days; CLD at 28 days or at 36 weeks' PMA; or CLD in survivors at 28 days or at 36 weeks' PMA. Prophylaxis with cromolyn sodium did not show a statistically significant difference in overall neonatal mortality, incidence of air leaks, necrotising enterocolitis, intraventricular haemorrhage, sepsis, and days of mechanical ventilation. No side effects were noted. Further research does not seem to be justified. AUTHORS' CONCLUSIONS There is currently no evidence from randomised trials that cromolyn sodium has a role in the prevention of CLD. Cromolyn sodium cannot be recommended for the prevention of CLD in preterm infants.
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Sodium cromoglycate and eformoterol attenuate sensitivity and reactivity to inhaled mannitol in subjects with bronchiectasis.
Briffa, PJ, Anderson, SD, Burton, DL, Young, IH
Respirology (Carlton, Vic.). 2011;(1):161-6
Abstract
BACKGROUND AND OBJECTIVE Dry powder mannitol has the potential to be used to enhance clearance of mucus in subjects with bronchiectasis. A reduction in FEV1 has been recorded in some subjects with bronchiectasis after inhaling mannitol. The aim of this study was to investigate if pre-medicating with either sodium cromoglycate (SCG) or eformoterol could inhibit this reduction in FEV1. METHODS A double-blind, placebo-controlled, randomized cross-over study was conducted. Lung function and airway response to mannitol was assessed on a control day and then re-assessed after pre-medication with placebo, SCG and eformoterol in nine subjects. Sensitivity to mannitol, expressed as the dose required to induce a 15% fall in FEV1 (PD15), and reactivity to mannitol, expressed as the % fall in FEV1 per mg of mannitol (response-dose ratio, RDR), are reported. RESULTS Subjects had an FEV1 of 68 ± 14% predicted, FVC of 97 ± 15% predicted and FEV1 /FVC of 71 ± 8%. They were mildly hypoxemic and the SpO2 was 95 ± 2%.They had a PD15 to mannitol of 235 mg (95% CI: 150-368 mg) and a RDR of 0.057% fall in FEV1 per mg (95% CI: 0.038-0.085). After pre-medication with SCG, PD15 increased (773 mg, P < 0.05) and RDR was reduced (0.013, P < 0.05). Pre-medication with eformoterol also resulted in an increased PD15 (1141 mg, P < 0.01) and a reduced RDR (0.009, P < 0.01). A small but significant decrease in SpO2 from baseline was noted after mannitol in the presence of SCG (P < 0.05). CONCLUSIONS Pre-medication with either SCG or eformoterol protects patients with bronchiectasis from developing a significant reduction in FEV1 after inhaling mannitol.
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The role of decongestants, cromolyn, guafenesin, saline washes, capsaicin, leukotriene antagonists, and other treatments on rhinitis.
Kushnir, NM
Immunology and allergy clinics of North America. 2011;(3):601-17
Abstract
Clinical symptoms of allergic and nonallergic rhinitis are similar despite the significant difference in underlying mechanisms. Over-the-counter (OTC) treatments can be used as effective and affordable therapeutic modalities when recommended by a physician. Adjunct treatments, such as herbal medicine, acupuncture and homeopathy, have become increasingly popular. Most of the treatments reviewed in this article are available OTC and are a likely choice for patients suffering from acute or chronic rhinitis. This article provides an overview of treatment suggestions, benefits, and side effects for available OTC, prescription drug, and alternative choices in addition to the therapies described in other articles.