Compressed sensing reconstruction improves sensitivity of variable density spiral fMRI.

PURPOSE: Functional MRI (fMRI) techniques that can provide excellent blood oxygen level dependent contrast, rapid whole brain imaging, and minimal spatial distortion are in demand. This study explored whether fMRI sensitivity can be improved through the use of compressed sensing (CS) reconstruction of variable density spiral fMRI. METHODS: Three different CS-reconstructed 1-shot variable density spirals were explored (corresponding to 28%, 35%, and 46% under-sampling), and compared with conventional 1-shot and 2-shot Archimedean spirals acquired using matched echo time and volume repetition time. fMRI maps were reconstructed with or without CS MRI and sensitivity was compared using identically matched voxels. RESULTS: The results demonstrated that an l1 -norm based CS reconstruction only led to an increase in functional contrast when applied to 28% under-sampled data. A whole brain t-contrast map revealed that 2-shot uniformly sampled spiral and 28% under-sampled spiral data reconstructed with CS yield equivalent sensitivity, even with matched echo time and volume repetition time CONCLUSION: VD spiral exhibits a useful operating range, in the region of 25-30% under-sampling, for which CS reconstruction can be used to increase the sensitivity of fMRI to brain activity. Using CS, VD acquisitions achieve the same sensitivity as 2-shot Archimedean acquisitions, but require only a single shot.

Sodium cromoglicate: an ineffective drug or meta-analysis misused?

Sodium cromoglicate (SCG) has been available since around 1970 for the treatment of asthma and other allergic disorders in both adults and children. It has been approved for use around the world. Over the period of its development, a number of different formulations were introduced. In 1999, a systematic review of SCG use in childhood asthma was carried out and reported initially as a poster. Further systematic reviews and papers followed from the same authors and finally a Cochrane Collaboration review was published in 2003. All concluded that SCG was ineffective in paediatric asthma. Both the British Thoracic Society Guidelines for the treatment of paediatric asthma and the Model List of Essential Drugs of the WHO now reflect these conclusions. This paper looks carefully at the conclusions of these systematic reviews and raises concerns about the interpretation of the results. These failed to take adequate account of the changes with time in both the formulations used and the age groups examined, and also failed to take adequate note of the totality of information available over all end-points. One primary end-point was based on only four out of the 24 studies included in the review. Rather than having no effect, it is demonstrated that a considerable body of evidence favours SCG compared to placebo and, far from being ineffective, the drug appears to be effective particularly in older children. This article replaces a previously published version. DOI: 10.1002/pst.258.

Retracted and replaced: Sodium cromoglicate: an ineffective drug or meta-analysis misused?

The following article from Pharmaceutical Statistics, Sodium cromoglicate: an ineffective drug or meta-analysis misused? by M. T. Stevens, A. M. Edwards, J. B. L. Howell published online on 15 March 2007 in Wiley InterScience (www.interscience.wiley.com), has been retracted by agreement between the author, the journal Editor in Chief, Steven Julious, and John Wiley & Sons, Ltd. The retraction has been agreed because the article is not yet ready for publication and an early version without revisions was published in error. Replacement article pending. Copyright (c) 2007 John Wiley & Sons, Ltd.

Efficacy and acceptability of a new topical skin lotion of sodium cromoglicate (Altoderm) in atopic dermatitis in children aged 2-12 years: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory allergic disease of children. The primary anti-inflammatory therapy is topical steroids. An effective treatment without the topical and systemic adverse effects of corticosteroids would be useful. Topical formulations of sodium cromoglicate have been researched in the past, but without consistent results. We report a trial of a new aqueous skin lotion of sodium cromoglicate (Altoderm) in children with AD. OBJECTIVES: To compare the efficacy, safety and acceptability of Altoderm lotion with a placebo control in the treatment of AD in children. METHODS: A double-blind, controlled study in which children aged 2-12 years with AD were randomized to 12 weeks of treatment with a lotion containing 4% sodium cromoglicate (Altoderm) or the lotion base. To be included subjects had to have a SCORAD score of > or = 25 and < or = 60 at both of two clinic visits 14 days apart. Subjects continued using existing treatment which included emollients and topical steroids. The primary outcome was the change in the SCORAD score. The two groups were compared for the change in the SCORAD score from the second baseline visit to the visit after 12 weeks of treatment using an analysis of variance. Secondary outcome measures included parents' assessment of symptoms, usage of topical steroids recorded on daily diary cards, and final opinions of treatment by parent and clinician. Parents were asked about adverse effects at each clinic visit and the responses recorded. RESULTS: Fifty-eight children were randomized to Altoderm and 56 to placebo and all were included in the intention-to-treat analysis. The mean +/- SD SCORAD scores at baseline were 41.0 +/- 9.0 (Altoderm) and 40.4 +/- 8.73 (placebo). These scores were reduced after 12 weeks by 13.2 (36%) with Altoderm and by 7.6 (20%) with placebo. The difference of 5.6 (95% confidence interval 1.0-10.3) is statistically significant (P = 0.018). Diary card symptoms improved with both treatments but the improvement was greater in the Altoderm-treated patients. Topical steroid usage was reduced in both groups and was larger in the Altoderm-treated patients. The differences were statistically significant for the mean of all symptoms, the overall skin condition and use of topical steroids. Those for itching and sleep loss were not. Treatment-related adverse events were reported in 11 subjects (Altoderm seven, placebo four). Most of these referred to irritation, redness and burning at the site of application. There were four reports of erythema and pruritus (Altoderm three, placebo one), and three reports of application site burning (Altoderm two, placebo one). None was reported as severe or very severe. CONCLUSIONS: These results show a clinically useful benefit of this sodium cromoglicate lotion in children with moderately severe AD.

Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial.

BACKGROUND: Allergic rhinitis is a common disease altering quality of life. Its treatment is well established and guidelines have been proposed. However, their efficacy has never been tested. The aim of the study was to validate the guidelines of the International Consensus on Rhinitis in the treatment of seasonal allergic rhinitis. METHODS: A multicenter, multinational, open label, parallel, randomized study compared two therapeutic strategies in seasonal allergic rhinitis during a 3-week treatment. General practitioners were randomized into two groups. In the first group of 224 patients, doctors followed guidelines from the International Consensus on Rhinitis. Depending on the severity of nasal and ocular symptoms defined using visual analogue scales, patients received ebastine (an oral antihistamine), triamcinolone acetonide (a topical corticosteroid) and/or ophthalmic nedocromil sodium (a topical ocular cromone). In the second group of 241 patients, general practitioners had a free choice of treatment. The primary efficacy end points were quality of life measured using the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ) and the symptom-medication scores assessed daily with an electronic dairy system. RESULTS: Adjusted mean total symptom scores over 21 days were 4.93 in the guidelines strategy group compared with 7.48 in the free-choice treatment group (P = 0.0001). Mean total scores in the RQLQ decreased by 2.19 in the guidelines group compared with a decrease of 1.79 in the free-choice treatment group (P = 0.0001). At 21 days, the least square mean difference in improvement in overall scores for RQLQ in the guidelines group compared with the free-choice treatment group was 0.53, which was greater than the minimal important difference. CONCLUSIONS: Patients with seasonal allergic rhinitis often present severe symptoms which are not well recognized or controlled by physicians using their own criteria of severity and treatment. Using a simple method for the evaluation of the severity and a simple therapeutic scheme based on International Guidelines, patients with seasonal allergic rhinitis presented a significant improvement by comparison with those receiving a non-standardized treatment.

A randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of a Chinese herbal product (P07P) for the treatment of canine atopic dermatitis.

A randomized, double-blind, placebo-controlled trial of P07P, a product derived from a traditional Chinese herbal remedy, was undertaken in 50 dogs with atopic dermatitis. Owners recorded a daily itch score for 4-14 days before treatment and during treatment. Packets of powder containing P07P or placebo were added to the food once daily for 8 weeks. Dogs were assessed for erythema, surface damage, overall coat condition and seborrhoea by the same investigator, as well as for pruritus and general demeanour, at 0 (visit 2), 28 (visit 3) and 56 (visit 4) days of treatment or at withdrawal. Investigator and owner assessments of response were recorded after 28 and 56 days of treatment or at withdrawal. The predefined primary outcome measure was the owners' assessment of response at the end of treatment. Nine of the 24 dogs (37.5%) in the P07P group but only 3 of the 23 dogs (13%) in the placebo group were considered to have improved, but this difference was not statistically significant (P = 0.09). There was a significantly higher withdrawal rate due to worsening of condition in the placebo group (P = 0.04). Mean daily itch score in the second 28-day period of the study was significantly higher than baseline in the placebo group (P = 0.01) but not in the P07P group (P = 0.30). Pruritus scores showed a significant deterioration from baseline at the final visit in the placebo group (P = 0.01) but not in the P07P group (P = 1.00). There was a significant difference between the groups in change from baseline in erythema score at visit 3 (P = 0.05). There were no significant differences (P > 0.05) in surface damage, seborrhoea, overall coat condition and general demeanour scores within or between the groups throughout the study. The product was well tolerated with no severe or serious adverse events recorded. P07P may be beneficial as a novel nonsteroidal therapy for the management of dogs with atopic dermatitis.

Clinical experience with Tilavist: an overview of efficacy and safety.

A programme of clinical studies was carried out to determine the basic efficacy and safety of 2% nedocromil sodium eye drops (Tilavist) in treating allergic conjunctivitis, in 2,905 patients from 3-76 years of age. Results of all the double-masked placebo comparative studies completed to date-five in vernal keratoconjunctivitis (VKC), five in perennial (PAC) and 16 in seasonal allergic conjunctivitis (SAC)-have been assessed in a statistical overview analysis. Nedocromil sodium, administered four times daily to 153 patients with VKC, was significantly more effective than placebo (155 patients) and in the clinicians' opinion gave good control in 76% of cases, compared with 46% for placebo (p < 0.001). Patients with chronic symptoms of PAC also responded better to nedocromil sodium given four times daily (n = 146) rather than twice daily (n = 86), and significantly more patients (p < 0.001) were effectively controlled by four times daily treatment with nedocromil sodium (72%) than with placebo (47%; n = 156). Twice-daily dosage with nedocromil sodium (n = 677) was adequate for SAC, however, and the treatment was statistically better than placebo (p < 0.01-p < 0.001) whether dosed twice or four times daily. Speed of action was assessed in seven SAC studies in which 79% of all patients (n = 295) using nedocromil sodium had experienced relief of symptoms when questioned, half of them within 15 minutes and 74% during the first hour after dosing. Test treatments were well-accepted by both adults and children, and there were no major adverse events. Minor irritations reported more frequently with nedocromil sodium than placebo were stinging or burning of the eyes on application of the drops and a distinctive taste, noted by 5% of the active treatment group (n = 1,552).

The clinical efficacy of inhaled nedocromil sodium (Tilade) in the treatment of asthma.

Inhaled nedocromil sodium, an anti-inflammatory agent for the maintenance treatment of asthma, has been the subject of many clinical trials but only a proportion have been published. This paper provides an overview analysis of all known placebo-controlled, double-blind, randomized therapeutic trials. Both single centre and multicentre trials are included. A comparison has been made between the treatment effects of nedocromil sodium and placebo, using six efficacy variables (day and night asthma, cough, mean daily peak expiratory flow rate, inhaled bronchodilator use, clinic lung function (forced expiratory volume in one second) and global opinion of treatment efficacy. One hundred and twenty seven trial centres, involving 4,723 patients, have been included. The results demonstrate the efficacy of inhaled nedocromil sodium in a variety of patients with asthma. Optimal effects are evident in patients with moderate asthma, currently receiving treatment with inhaled and oral bronchodilators.

Synergistic activity of sodium cromoglycate and beta 2-stimulants in rat lung anaphylaxis.

Using a model of passive anaphylactic bronchoconstriction in the rat, the combined inhibitory effects of sodium cromoglycate and the beta 2-adrenoceptor agonists fenoterol and salbutamol were shown to be synergistic. Synergism was most evident in animals strongly sensitised with relatively high levels of IgE antibodies, in which the individual drugs showed reduced potency.

Evaluation of the effect of food on the absorption of sustained-release theophylline and comparison of two methods for serum theophylline analysis.

Fifteen healthy volunteers took part in a study to investigate the effect of food on the bioavailability of a slow-release formulation of theophylline. Serum theophylline levels were measured every two hours for ten hours after a single oral dose of 500 mg of theophylline. Serum levels were significantly higher after the dose was taken on an empty stomach; however, serum levels were significantly higher 10 hours later when the dose was taken after a standard meal. Despite these differences, eating had no overall effect on theophylline bioavailability. Two analytic methods for measuring serum levels of theophylline were compared, and it was found that fluorometry could measure lower levels and was therefore more precise than an enzyme immunoassay method, which is probably due to the complete automation and reduced interference of bilirubin and hemoglobin.

Evaluation of organ weight differences in toxicological experiments.

The most frequent measure used to interpret drug effects on organ weights in toxicological experiments is the ratio of the organ weight to the animal's bodyweight. It is shown that in general this measure is not useful and can lead to erroneous conclusions regarding drug effects, specifically for rats. In addition a new approach to the design of organ weight experiments is considered and compared to the use of relative weights using simulated data. It is concluded that this new method may be useful in the evaluation of organ weights.

An alternative method for the evaluation of organ weight experiments.

Previous work has suggested that the use of relative organ weights can lead to erroneous conclusions in toxicological experiments. A method of analysis involving very little extra experimentation is suggested and evaluated. Simulated results from rat organ weights indicate that the method is superior to the use of relative organ weights and leads to reliable conclusions being drawn about the treatment effects.

The value of relative organ weights.

It is accepted practice in presenting organ weight data to express the results relative to the animal's body weight. The data presented suggest that in rats no benefits are obtained from this method either in reducing the variability of the data or in removing bias due to different body weights. By using simulated data it is further shown that relative weights can lead to erroneous conclusions and misinterpretation of drug effects and it is concluded that workers should present their results in absolute as opposed to relative weights.