Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium.

The efficacy and safety of salmeterol alone was compared with the combination of salmeterol plus ipratropium and with placebo during long-term treatment in patients with stable chronic obstructive pulmonary disease. In addition, the single-dose effect in response to the first dose of treatment was studied over 12 h. The patients (n=144; age 64+/-7 yrs, forced expiratory volume in one second (FEV1) 44+/-11% pred) participated in a three-centre double-blind double-placebo parallel group study and were randomized after a run-in period of 2 weeks to receive either salmeterol 50 microg b.i.d., salmeterol 5 microg b.i.d. plus ipratropium 40 microg q.i.d. or placebo for a period of 12 weeks. The single-dose study demonstrated that salmeterol produced a significant increase in FEV1 (peak of 7% pred) and specific airway conductance (sGaw) (maximum of 60% baseline) for > or =12 h. The combination of salmeterol plus ipratropium elicited a greater bronchodilator response (11% and 94% increases respectively) than salmeterol alone during the first 6 h after inhalation. During treatment there were significant improvements in daytime symptom scores and morning peak expiratory flow in both the salmeterol and the salmeterol plus ipratropium groups (p<0.001), with an associated decrease in the use of rescue salbutamol. Improvements in FEV1 and sGaw were greater in the salmeterol plus ipratropium group than in the patients receiving only salmeterol. Thirty-five patients had an exacerbation; 11 (23%) in the salmeterol group (versus placebo NS), six (13%) in the salmeterol plus ipratropium group (versus placebo p<0.01) and 18 (36%) in the placebo group. In conclusion, in patients with severe stable chronic obstructive pulmonary disease, long-term treatment with either salmeterol alone or salmeterol plus ipratropium is safe and effective. There was added benefit from the combination therapy in terms of improvement in airways obstruction, but not for improvement in symptom control or need for rescue salbutamol.

Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action.

We evaluated the profile of the bronchodilatory effect of three inhaled beta2-agonists, 24 microg formoterol, 50 microg salmeterol and 200 microg salbutamol, in patients with stable, moderately severe asthma. Thirty asthmatics (mean+/-SD age 54+/-8 yrs; forced expiratory volume in one second (FEV1) 58+/-12% predicted; reversibility of FEV1 21+/-8% from baseline) participated in a single-centre, double-blind, randomized, single-dose, cross-over study. FEV1 was obtained in baseline condition and 10, 20, 30, 60 min, and every hour up to 12 h after inhalation of the trial drug. Specific airway conductance (sGaw) was measured at baseline condition and 1, 3, 5, 7, 10, 20, 30, 60 min, and every hour up to 12 h after inhalation. Formoterol produced a mean increase in sGaw (as % of baseline) of 44% after 1 min, maximal (135%) after 2 h, and 56% after 12 h. The mean increase in FEV1 was maximal (27%) after 2h, and 10% after 12 h. After salmeterol, mean increase in sGaw amounted to 16% after 3 min, maximal (111%) after 2-4 h, and 58% after 12 h. The mean increase in FEV1 was maximally 25% after 3h, being 11% after 12 h. After salbutamol, mean increase in sGaw was 44% after 1 min and maximal (100%) after 30 min. The peak increase in FEV1 was 25%. We conclude that formoterol (24 microg) and salmeterol (50 microg) had an equal bronchodilatory capacity, which was similar to that of 200 microg salbutamol and lasted for at least 12 h in patients with asthma. However, formoterol had a more rapid onset of action than salmeterol, equal to that of salbutamol.

Comparison of performance of four instruments in evaluating the effects of salmeterol on asthma quality of life.

Quality of life measures are increasingly used as important efficacy endpoints in studies of drugs for asthma. The purpose of this study was to assess both the sensitivity to change and the construct validity of four different quality of life instruments in patients with asthma. In a double-blind, parallel group study, 120 moderate asthma patients, aged between 18-70 yrs, received either inhaled salmeterol 50 micrograms b.i.d. or inhaled salbutamol 400 micrograms b.i.d. In addition to respiratory outcomes, quality of life was measured at a 6 weeks follow-up using: 1) Asthma Quality of Life Questionnaire (AQLQ); 2) Living With Asthma Questionnaire (LWAQ); 3) Sickness Impact Profile (SIP); 4) Rating Scale (RS); and Standard Gamble (SG) utilities. Salmeterol led to significant improvements over salbutamol on virtually all clinical outcomes. Although all the quality of life instruments showed the same trend in favour of salmeterol, only the AQLQ and RS utilities showed significantly greater improvement on salmeterol than on salbutamol. Except for the AQLQ, the correlation between change in lung function and change in quality of life was generally low. Whereas, the AQLQ correlated well with the patient's overall assessment of efficacy (r = 0.64), the LWAQ, SIP and utilities failed to show such a correlation. The AQLQ showed the best correlation with symptom scores. The cross-sectional correlation between the AQLQ and the LWAQ was 0.73, whereas the longitudinal correlation was only 0.29. The SG generally showed poor correlation with other measures, including the RS. In conclusion, patients given salmeterol showed a greater improvement in quality of life compared to patients given salbutamol. Of the disease-specific questionnaires the Asthma Quality of Life Questionnaire was found to be more responsive to change than the Living With Asthma Questionnaire and showed greater validity. Of the generic instruments, the rating scale utilities were most responsive. The Standard Gamble showed poor correlation with other measures.

The promoter for a variant surface glycoprotein gene expression site in Trypanosoma brucei.

The variant-specific surface glycoprotein (VSG) gene 221 of Trypanosoma brucei is transcribed as part of a 60 kb expression site (ES). We have identified the promoter controlling this multigene transcription unit by the use of 221 chromosome-enriched DNA libraries and VSG gene 221 expression site specific transcripts. The start of transcription was determined by hybridization and RNase protection analysis of nascent RNA. The 5' ends of the major transcripts coming from the initiation region map at nucleotide sequences that do not strongly resemble rRNA transcriptional starts even though the transcripts are synthesized by an RNA polymerase highly resistant to alpha-amanitin. The cloned VSG gene 221 ES transcription initiation region promotes high CAT gene expression, when reintroduced by electroporation into T. brucei. We show that the activity of this expression site is controlled at or near transcription initiation in bloodstream trypanosomes. The 221 ES is inactivated without any sequence alteration within 1.4 kb of the transcription start site. This excludes mechanisms of promoter inactivation involving DNA rearrangements in the vicinity of the transcription start site, e.g. promoter inversion or conversion.