Inhaled salmeterol in the treatment of patients with moderate to severe reversible obstructive airways disease--a 3-month comparison of the efficacy and safety of twice-daily salmeterol (100 micrograms) with salmeterol (50 micrograms).

Three-hundred and fifty patients with moderate to severe reversible obstructive airways disease (forced expiratory volume in 1 s or peak expiratory flow rate < or = 50% predicted, a 15% reversibility to inhaled salbutamol and symptomatic) were recruited into a multi-centre, multinational, double-blind, parallel-group randomized study. Two-hundred and eighty-three patients were randomized to receive 50 micrograms salmeterol twice daily or 100 micrograms salmeterol twice daily administered from a metered-dose inhaler for 3 months. Salbutamol (100 micrograms per metered actuation) was provided for symptomatic relief. Morning and evening peak expiratory flow rate (PEFR), day-time and night-time asthma symptoms and additional bronchodilator usage were recorded by the patient on a daily basis. Lung function and patient/physician assessment of treatment efficacy were recorded at scheduled clinic visits. Safety was determined by monitoring adverse events and standard biochemical, haematological and cardiovascular parameters. Salmeterol 100 micrograms twice daily was consistently superior to salmeterol 50 micrograms twice daily in morning and evening PEFR measurements (mean differences between the treatments: 10-14 l min-1 for morning, 95% CI-0, 22 l min-1, P = 0.047; and 10-15 l min-1 for evening, 95% CI 2, 22 l min-1, P = 0.023). The improvement in PEFR was independent of concurrent steroid usage, with the most marked improvement being seen in the more severe asthmatics requiring concurrent oral corticosteroids (mean differences between the treatments: 27-31 l min-1, 95% CI: 3,55 l m-1, P = 0.027).(ABSTRACT TRUNCATED AT 250 WORDS)

Adapting the buccal micronucleus cytome assay for use in wild birds: age and sex affect background frequency in pigeons.

Micronucleus (MN) formation has been used extensively as a biomarker of damage from genotoxic exposures. The Buccal MN Cytome (BMCyt) assay provides a noninvasive means of quantifying MN frequency in humans, but it has not been developed for use in wildlife. We adapted the BMCyt assay for use in wild birds, with a focus on feral pigeons (Columba livia) as a potential indicator species. Five of six urban bird species sampled using oral cavity swabs produced sufficient buccal cells for the BMCyt assay. The body size of species sampled ranged almost 100-fold (~60 to 5,000 g), but was a not major factor influencing the number of buccal cells collected. Pigeon cells were stained and scored following published BMCyt assay protocols for humans, but with a modified fixation approach using heat and methanol. Pigeons had the same common nuclear abnormalities reported in human studies, and a similar background MN formation frequency of 0.88 MN/1,000 cells. Adult pigeons had on average a threefold higher rate of MN formation than juveniles, and males had a 1.4- to 2.2-fold higher frequency than females. Domestic and feral pigeons did not differ in overall MN frequency. Our results indicate that the BMCyt assay can be used on wild birds, and could provide a means of assessing environmental genotoxicity in pigeons, a useful indicator species. However, bird age and sex are important factors affecting background MN frequency, and thereby the design of environmental studies.

Formats for peer review of dynamic psychotherapy.

The mental health field must deal with peer review as a fact of life. However, many providers do not understand how to describe the nature or process of the psychotherapy they use, and many peer reviewers seem to lack knowledge of what constitutes a given modality of psychotherapy. If clear definitions of the different modes of dynamic psychotherapy are available--and in fact the literature shows substantial agreement on such aspects as patient selection, time frames, goals, and techniques--formats for the peer review of each modality will naturally follow. The author presents definitions and peer review formats for symptom-relief, supportive, focal, and long-term exploratory psychotherapy.

Efficacy of meropenem in experimental meningitis.

Meropenem and comparator antibiotics, including ceftriaxone, ceftazidime, benzyl penicillin and a combination of ampicillin plus gentamicin, were evaluated in a model of bacterial meningitis in the guinea-pig. The model is an acute infection in which challenge with each organism, if untreated, causes an increase in numbers of white blood cells, elevation of protein concentrations and 6-8 log10 cfu/mL of bacteria in the CSF. Infections caused by Haemophilus influenzae, Neisseria meningitidis, three strains of Streptococcus pneumoniae (two penicillin-resistant), Escherichia coli, Pseudomonas aeruginosa and Listeria monocytogenes all responded to meropenem, which was as active as the comparator agents in all studies, and was more active in most. Of particular note were the results seen against S. pneumoniae (penicillin-resistant) infections, in which meropenem was significantly more effective than ceftriaxone. Also notable were results from the P. aeruginosa infection where meropenem, at low doses, was more effective than ceftazidime. Activity against L. monocytogenes was equivalent to that produced by treatment with the combination of ampicillin plus gentamicin, even when treatment was delayed. These results show that, in an animal model, meropenem penetrates into CSF in concentrations sufficient to produce significant reductions in the numbers of common and less common pathogens.

Kinetics of prostacyclin synthetase in umbilical artery microsomes from normal and pre-eclamptic pregnancies.

1 Prostacyclin synthetase in umbilical artery microsomes obeys Michaelis-Menten kinetics. 2 The maximum velocity (Vmax) of prostacyclin synthetase prepared from normal umbilical arteries was significantly higher than the Vmax of prostacyclin synthetase in umbilical arteries taken from pre-eclamptic pregnancies. 3 The Michaelis-Menten constant (Km) of the two prostacyclin synthetase preparations was significantly different with the synthetase from pre-eclamptic arteries have a higher affinity for substrate. 4 The limiting factor for prostacyclin synthesis is Vmax at high substrate concentrations which appears to be the case in umbilical arteries. However, at low substrate concentration there would be no difference in prostacyclin synthesis by the two forms of prostacyclin synthetase.

Regular versus symptomatic aerosol bronchodilator treatment of asthma.

Regular treatment with salbutamol or placebo aerosols was compared in a double-blind study in 18 asthma patients. Although symptom scores and respiratory function tests were not significantly different, wheezing attacks requiring additional puffs of a standard salbutamol aerosol were significantly more frequent during the period on placebo when patients were receiving symptomatic treatment only. Thus regular treatment with bronchodilator aerosols provides better control of asthma than symptomatic use alone.

Epoprostenol (prostacyclin, PGI2) binding and activation of adenylate cyclase in platelets of diabetic and control subjects.

1 The binding of epoprostenol (prostacyclin, PGI2) to isolated fractured human platelets has been studied using tritiated PGI2. 2 High and low affinity binding sites for PGI2 have been identified (Kd values = 16 and 382 nM). 3 Analysis of the prostacyclin-dependent activation of adenylate cyclase suggests that enzyme activation is mediated by the high affinity binding site. 4 Platelet PGI2 receptor binding and adenylate cyclase activation by PGI2 are unchanged in diabetic and normal human platelets. 5 This work suggests that hyperaggregability of diabetic platelets is not due to any alteration of platelet prostacyclin receptor numbers or their activation.

Cardiovascular and platelet effects in man of BW 245C, a stable mimic of epoprostenol (PGI2).

1 BW 245C is a stable hydantoin prostaglandin analogue with a biological action similar to epoprostenol (PGI2). 2 Intravenous BW 245C (1,2 and 4 ng kg-1 min-1) produced a progressive increase in heart rate and pulse pressure in four healthy male volunteers. 3 These changes in heart rate and pulse pressure were accompanied by reduced ex vivo platelet aggregation to submaximal concentrations of ADP. 4 In man, BW 245C has a profile of action and potency similar to PGI2. However, it has a longer duration of action than PGI2.

Does a selective adenosine A(1) receptor agonist protect against exercise induced ischaemia in patients with coronary artery disease?

BACKGROUND: The "warm up" effect in angina may represent ischaemic preconditioning, which is mediated by adenosine A(1) receptors in most models. OBJECTIVE: To investigate the effect of a selective A(1) agonist, GR79236 (GlaxoSmithKline), on exercise induced angina and ischaemic left ventricular dysfunction in patients with coronary artery disease. DESIGN: A double blind crossover study. PATIENTS: 25 patients with multivessel coronary artery disease. INTERVENTIONS: On mornings one week apart, patients received intravenous GR79236 10 microgram/kg or placebo, and then carried out two supine bicycle exercise tests separated by 30 minutes. Equilibrium radionuclide angiography was done before and during exercise. RESULTS: The onset of chest pain or 1 mm ST depression was delayed and occurred at a higher rate-pressure product during the second exercise test following either placebo or GR79236. Compared with placebo, GR79236 did not affect these indices during equivalent tests. GR79236 reduced resting global ejection fraction from (mean (SD)) 63 (7)% to 61 (5)% (p < 0.05) by a selective reduction in the regional ejection fraction of "ischaemic" left ventricular sectors (those where the ejection fraction fell during the first exercise test following placebo). Ischaemic sectors showed increased function during the second test following placebo (72 (21)% v 66 (20)%; p = 0.0001), or during the first test following GR79236 (69 (21)% v 66 (20)%; p = 0.0001). Sequential exercise further increased the function of ischaemic sectors even after drug administration. CONCLUSIONS: GR79236 failed to mimic the warm up effect, and warm up occurred even in the presence of this agent. This suggests that ischaemic preconditioning is not an important component of this type of protection. The complex actions of the drug on regional left ventricular function at rest and during exercise suggest several competing A(1) mediated actions.