Dose equivalence and bronchoprotective effects of salmeterol and salbutamol in asthma.

BACKGROUND: Salbutamol is the most widely prescribed short acting beta 2 agonist and salmeterol is the first long acting inhaled beta 2 agonist. The dose equivalence of salmeterol and salbutamol is disputed. Estimates of weight-for-weight dose ratio have ranged from 1:2 to 1:16. A study was undertaken to clarify the true dose ratio. METHODS: The bronchoprotection afforded against repeated methacholine challenge by inhaled salmeterol 25 micrograms and 100 micrograms and salbutamol 100 micrograms and 400 micrograms was compared in a randomised, double blind, placebo controlled, crossover trial. Subjects were 16 stable asthmatics with a baseline forced expiratory volume in one second (FEV1) of > or = 65% predicted, screening concentration provoking a fall in FEV1 of 20% (PC20FEV1) of < or = 8mg/ml, and a shift in PC20FEV1 of more than two doubling concentration steps following inhalation of salbutamol 400 micrograms. On five separate occasions subjects underwent methacholine challenge before and 30 and 120 minutes after drug administration. PD20FEV1 was calculated for each challenge. FEV1 at 90 minutes after drug administration was also recorded. RESULTS: Bronchoprotection afforded by salmeterol was increased at 120 minutes compared with 30 minutes and protection by salbutamol was decreased. Protection by both doses of salmeterol was similar to salbutamol 100 micrograms at 30 minutes but significantly greater at 120 minutes. FEV1 at 90 minutes was significantly greater after salmeterol 100 micrograms than after placebo, but there were no other significant differences between treatments. Maximal observed protection was equivalent for salmeterol 100 micrograms and salbutamol 400 micrograms. CONCLUSIONS: The data are compatible with a weight-for-weight dose ratio for salmeterol:salbutamol of < or = 1:4.

Effects of regular salmeterol on lung function and exercise capacity in patients with chronic obstructive airways disease.

BACKGROUND: The aim of this study was to evaluate the effects of single and chronic dosing with salmeterol on exercise capacity and lung function in patients with chronic obstructive pulmonary disease. METHODS: Twenty nine patients of mean (SE) age 64 (1.5) years, forced expiratory volume in one second (FEV1) 42(3)% of predicted, and 5-15% reversibility to salbutamol 200 micrograms were randomised to receive four weeks treatment with salmeterol 50 micrograms twice daily or placebo in a double blind crossover fashion with a one week washout period in between. Measurements of spirometric parameters, static lung volumes, and exercise capacity were made one and six hours after a single dose, and six hours after the final dose of salmeterol or placebo. RESULTS: Salmeterol produced a small increase in FEV1 at one and six hours after a single dose, and this was maintained after chronic dosing (mean difference and 95% CI versus placebo): single dosing at one hour 0.07 (95% CI 0.02 to 0.11) 1, single dosing at six hours 0.16 (95% CI 0.09 to 0.22) 1, chronic dosing at six hours 0.11 (95% CI 0.03 to 0.19) 1. The increase in forced vital capacity (FVC) was greater with salmeterol than with placebo six hours after single but not chronic dosing: single dosing at six hours 0.17 (95% CI 0.04 to 0.29) 1, chronic dosing at six hours 0.02 (95% CI -0.18 to 0.22) 1. Slow vital capacity was increased after treatment with salmeterol compared with placebo one and six hours after single but not after chronic dosing. There were no significant differences in static lung volumes or exercise capacity after single or chronic dosing with salmeterol compared with placebo. Patients reported a significantly lower Borg score for perceived exertion following the six minute walk after chronic treatment with salmeterol compared with placebo. CONCLUSIONS: Salmeterol produced a small improvement in spirometric values compared with placebo consistent with the degree of reversibility originally shown by the subjects to salbutamol 200 micrograms. This was not associated with improvements in static lung volumes or exercise capacity, but there was some symptomatic benefit in that patients were able to walk the same distance in six minutes with less perceived exertion.

A 4-week comparison of salmeterol and terbutaline in adult asthma.

This was a 4-week, open-label, parallel-group study designed to compare the efficacy and safety of the long-acting inhaled bronchodilator, salmeterol, with the established inhaled bronchodilator, terbutaline, in the treatment of patients with mild to moderate asthma. A total of 243 adult patients was randomized to receive treatment with either salmeterol 50 micrograms bd via a Diskhaler (Glaxo) inhaler (n = 121) or terbutaline 500 micrograms qds via a reservoir powder inhaler device (n = 122). Apart from all bronchodilator treatment which was withdrawn at the start of the run-in period and replaced by inhaled salbutamol to be used as required for symptom relief, all concurrent medications were kept constant throughout the study. Salmeterol produced a significantly greater increase in mean morning peak expiratory flow (PEF) than terbutaline (difference in adjusted means after treatment = 28 l/min; 95% CI = 19-37 l/min; P < 0.001). Likewise, the increase in mean evening PEF was significantly greater following treatment with salmeterol than with terbutaline (difference in adjusted means = 9 l/min; 95% CI = 0-17 l/min; P = 0.045). Salmeterol was associated with a significant reduction in diurnal variation in PEF by comparison with terbutaline (difference in adjusted means = -18 l/min; 95% CI = -24, -12 l/min; P < 0.001). Significant improvements with salmeterol by comparison with terbutaline were also observed in daytime and night-time asthma scores, percentage of symptom-free days and nights, use of additional inhaled bronchodilator, and percentage of days and nights when no additional inhaled bronchodilator was needed.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of rotavirus-specific cytotoxic T lymphocytes by vaccinia virus recombinants expressing individual rotavirus genes.

We determined the capacity of vaccinia virus recombinants expressing individual rotavirus genes to induce virus-specific cytotoxic T lymphocytes (CTLs) in mice. Mice were orally inoculated with vaccinia virus recombinants containing genes which encode rotavirus outer capsid proteins vp4 or vp7, single-shelled virus proteins vp1, vp2, or vp6, or rotavirus nonstructural proteins NS53, NS35, NS28, or NS26/NS12. We found that (i) the greatest frequencies of virus-specific CTLs were induced by vaccinia virus recombinants expressing vp7, (ii) transport of vp7 beyond the endoplasmic reticulum was not necessary for induction of CTLs, (iii) recombinants expressing vp7 induced CTLs which reacted with different rotavirus serotypes, and (iv) CTLs were induced among both intestinal and nonintestinal lymphocytes after oral inoculation. These findings may be relevant to vaccine strategies which utilize vectors expressing individual rotavirus genes.

Outer capsid glycoprotein vp7 is recognized by cross-reactive, rotavirus-specific, cytotoxic T lymphocytes.

Cytotoxic T lymphocytes (CTLs) generated in mice orally inoculated with rotaviruses lyse target cells infected with different rotavirus serotypes (cross-reactive CTLs). Using vaccinia virus recombinants expressing individual rotavirus proteins from two different rotavirus serotypes, we found that cross-reactive CTLs recognize target cells expressing outer capsid protein vp7 better than those expressing outer capsid protein vp4 or inner capsid protein vp6. These findings may be relevant to vaccine strategies which include immunization with reassortant rotaviruses or viral or bacterial vectors expressing individual rotavirus proteins. The region or regions of vp7 which are antigenically conserved among different rotavirus serotypes and recognized by cross-reactive CTLs remain to be determined.

Increases in Na/K pump numbers in isolated human lymphocytes exposed to lithium in vitro. Reversal by myo-inositol and by inhibitors of protein kinase C and the Na/H antiport.

Lithium (1-8 mM) caused a dose-dependent increase in the number of [3H]ouabain binding sites and in sodium/potassium (Na/K) pump activity in normal lymphocytes after incubation for 72 h. The increase in Na/K pump activity was due to an increase in the Vmax of the pump, with no change in the apparent affinity (Km) for potassium (rubidium). There was no change in the turnover number of the pump and the intracellular sodium concentration fell. The increase in [3H]ouabain binding sites was prevented by the addition of myo-inositol (10 mM), by inhibition of the protein kinase C with staurosporine (100 nM) and by inhibition of the Na/H antiport with dimethylamiloride (50 microM). These results suggest that the increase in Na/K pump activity caused by lithium is due to an increase in pump numbers and not due to increased activity of individual pumps or to an alteration in the affinity of the pumps for potassium. The increase in Na/K pump numbers and activity in lymphocytes exposed to lithium for 72 h may be related to altered Na/H antiport activity secondary to inhibition of phosphoinositol breakdown by lithium.

Impact ejecta horizon within late precambrian shales, adelaide geosyncline, South australia.

A solitary layer of shattered crustal rock fragments has been traced over a distance of 260 kilometers within folded 600-million-year-old Precambrian marine shales of the Adelaide Geosyncline, South Australia. The fragments consist entirely of acid to intermediate volcanics (approximately 1575 million years old) displaying shattered mineral grains, shock lamellae in quartz, and small shatter cones. Fragments reach 30 centimeters in diameter and show evidence of vertical fall emplacement. Available evidence points to derivation of the rock fragments from a distant hypervelocity impact into the Gawler Range Volcanics at Lake Acraman, approximately 300 kilometers west of the Adelaide Geosyncline.