Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost-effectiveness study.

OBJECTIVE: To evaluate efficacy and cost-effectiveness of budesonide/formoterol (Symbicort) maintenance (one dose once or twice daily) plus additional doses as needed (Symbicort Maintenance And Reliever Therapy, SMART) compared with a higher fixed dose of budesonide/formoterol with formoterol as needed in patients with persistent asthma. STUDY DESIGN AND METHODS: 6-month, open, randomised study of 465 patients either not well controlled on an inhaled corticosteroid (ICS), or well controlled on a combination of ICS and a long-acting beta(2)-agonist (LABA). TREATMENTS: budesonide/formoterol 160/4.5 microg, one inhalation, once or twice daily maintenance plus additional doses as-needed (1 x SMART or 2 x SMART), or budesonide/formoterol 160/4.5 microg two inhalations twice daily plus formoterol 4.5 microg as needed (2 x 2 FIX + F). Children 6-11 years old used an 80/4.5 microg dose strength. Primary variables of efficacy were the changes in the Asthma Control Questionnaire (ACQ(5)) and morning peak expiratory flow (PEF). RESULTS: Mean age of patients 40 years (range 6-82 years); 53% female. No differences between the groups were found in ACQ(5) scores or asthma exacerbation rates. Morning PEF was higher in the 2 x 2 FIX + F group vs. the 1 x SMART and 2 x SMART groups (differences 13 L/min and 9 L/min, respectively; p < 0.002). The 1 x SMART group showed a significant decrease in asthma controlled days compared with the two other groups. No difference was seen between the 2 x SMART group and the 2 x 2 FIX + F group. Treatment costs were significantly lower in the SMART groups compared with the 2 x 2 FIX + F group. CONCLUSION: Compared with the 2 x 2 FIX + F treatment the use of budesonide/formoterol was 30-40% lower in the SMART groups while maintaining equal ACQ(5) scores. Daily asthma control improved equally with 2 x SMART compared to 2 x 2 FIX + F with a reduction in asthma medication cost. The one dose once daily maintenance treatment (1 x SMART) resulted in a low level of treatment failure (exacerbations) but led to more days with symptoms. Therefore, a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma.

Development of a solid-phase extraction/gas chromatographic-mass spectrometric method for quantification of succinic acid in nucleoside derivatives for oligonucleotide synthesis.

A solid-phase extraction (SPE)/gas chromatographic-mass spectrometric (GC-MS) method was developed for analysing residual succinic acid in nucleoside derivatives to be used in oligonucleotide synthesis. Use of a SPE protocol, enabled most of the derivatives to be trapped, thereby creating eluates enriched in succinic acid. GC-MS was used to quantify the amount of residual succinic acid in four different nucleoside preparations, with succinate concentrations varying from 0.18 to 0.24% (w/w). The within-day repeatability of the method was found to be 1.25% RSD. A linear relationship was observed between the amount of succinic acid in the sample and the GC-MS peak area, with a correlation coefficient of 0.9997 in the concentration interval 0.05-2.5% (w/w). Recoveries were measured by the addition of internal standards to working solutions and varied between 99.8 and 102.6%.

Short-term safety and tolerability of double-dose salmeterol/fluticasone propionate in adult asthmatic patients.

INTRODUCTION: The incidence of asthma exacerbations in patients receiving salmeterol/fluticasone propionate (Seretidetrade mark or Advair((R))) is low. However, when asthma control deteriorates, clinicians may instruct patients to double the dose of their inhaled corticosteroid medication for a short period. The purpose of this study was to demonstrate that doubling the dose of Seretidetrade mark for a period of 2 weeks in subjects with persistent asthma is safe and well tolerated. METHODS: This randomised, double-blind, parallel-group study was conducted in primary-care centres. Adults with a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of >/=70% predicted were stratified to receive a single dose of Seretidetrade mark 50mug/100mug, 50mug/250mug or 50mug/500mug twice daily from a Diskustrade mark inhaler for a 4-week run-in period, dependent on the dose of inhaled corticosteroid on entry. Subjects were then randomised to receive either an extra inhalation of the same dose of Seretidetrade mark received during the run-in (double dose) or an inhalation of matching placebo (single dose) for 14 days in a 2 : 1 ratio. Subjects were asked to record any adverse events, morning and evening heart rate (HR), peak flow and relief medication use in daily record cards. The primary endpoint was tremor as perceived by the subject. Clinic evaluations included HR, 12-lead ECG, and potassium and glucose levels. RESULTS: 110 and 208 subjects received single- and double-dose Seretidetrade mark, respectively. Only one subject experienced tremor. This was classified as mild and occurred in a subject receiving double-dose Seretidetrade mark (50mug/100mug). There was no difference between the treatment groups in the incidence of tremor (difference <1%; 95% CI -6, 8). Other salmeterol-related adverse events (palpitations, muscle cramps and headache) and fluticasone propionate-related events (oral candidiasis and hoarseness) occurred in a similar percentage of subjects in each treatment group. The treatment differences for morning and evening HR measurements showed small differences between the two groups (<2 beats/min). The adjusted mean treatment difference (double dose - single dose) in morning HR was 1.1 beats/min (95% CI 0.2, 2.0) and evening HR was 0.9 beats/min (95% CI 0.1, 1.7). Seven percent of subjects receiving single-dose Seretidetrade mark and 8% receiving double-dose Seretidetrade mark had a QTc change from baseline in the interval 30-59 msec. No increases above 59 msec were seen in either group. There were no clinically significant changes from baseline for potassium levels. Two percent of subjects in the single dose and <1% in the double-dose group had a change from a non-clinically significant baseline blood glucose assessment to a clinically significant abnormality at the end of treatment. CONCLUSION: In circumstances in which a physician may be considering doubling the dose of Seretidetrade mark for a short period of time in adult asthmatics, this study demonstrates that doubling the dose for a period of 2 weeks is safe and well tolerated.

Formation of new bioactive organic nitrites and their identification with gas chromatography-mass spectrometry and liquid chromatography coupled to nitrite reduction.

Nitric oxide (NO) donors, notably organic nitrates and nitrites are used therapeutically but tolerance develops rapidly, making the use of e.g. nitroglycerin difficult. NO donation in the pulmonary vascular bed might be useful in critically ill patients. Organic nitrites are not associated with tachyphylaxis but may induce methaemoglobinemia and systemic hypotension which might hamper their use. We hypothesised that new lung-selective NO donors can be identified by utilizing exhaled NO as measure for pulmonary NO donation and systemic arterial pressure to monitor hypotension and tolerance development. Solutions of alcohols and carbohydrates were reacted with NO gas and administered to ventilated rabbits for evaluation of in vivo NO donation. Chemical characterization was made by liquid chromatography with on-line nitrite reduction (LC-NO) and by gas chromatography-mass spectrometry (GC-MS). In vivo experiments showed that the hydroxyl-containing compounds treated with NO gas yielded potent NO donors, via nitrosylation to organic nitrites. Analyses by LC-NO showed that the reaction products were able to release NO in vitro. In GC-MS the reaction products were determined to be the organic nitrites, where some are new chemical entities. Non-polar donors preferentially increased exhaled NO with less effect on systemic blood pressure whereas more polar molecules had larger effects on systemic blood pressure and less on exhaled NO. We conclude that new organic nitrites suitable for intravenous administration are produced by reacting NO gas and certain hydroxyl-containing compounds in aqueous solutions. Selectivity of different organic nitrites towards the pulmonary and systemic circulation, respectively, may be determined by molecular polarity.