Search

The FACET (Formoterol and Corticosteroid Establishing Therapy) study established that there is a clear clinical benefit in adding formoterol to budesonide therapy in patients who have persistent symptoms of asthma despite treatment with low to moderate doses of an inhaled corticosteroid. We combined the clinical results from the FACET study with an expert survey on average resource use in connection with mild and severe asthma exacerbations in the U.K., Sweden and Spain. The primary objective of this study was to assess the health economics of adding the inhaled long-acting β₂-agonist formoterol to the inhaled corticosteroid budesonide in the treatment of asthma. The extra costs of adding the inhaled β₂-agonist formoterol to the corticosteroid budesonide in asthmatic patients in Sweden were offset by savings from reduced use of resources for exacerbations. For Spain the picture was mixed. Adding formoterol to low dose budesonide generated savings, whereas for moderate doses of budesonide about 75% of the extra formoterol costs could be recouped. In the U.K., other savings offset about half of the extra cost of formoterol. All cost-effectiveness ratios are within accepted cost-effectiveness ranges reported from previous studies. If productivity losses were included, there were net savings in all three countries, ranging from Euro 267–1183 per patient per year. In conclusion, adding the inhaled, long-acting β₂-agonist formoterol to low–moderate doses of the inhaled corticosteroid budesonide generated significant gains in all outcome measures with partial or complete offset of costs. Adding formoterol to budesonide can thus be considered to be cost-effective. Copyright 2001 HARCOURT PUBLISHERS LTD.

Activation-induced death of inflammatory cells (AICD) has an important function in immune maintenance. Type 1 Th cells are known to be more susceptible to AICD than Th2 cells. In the current study we examined whether NO-induced apoptosis also preferentially eliminates Th1 cells over Th2 cells. Naive human Th lymphocytes (CD4(+)CD45RO(-)) were activated in vitro for 1 week in the presence of IL-12 plus anti-IL-4 or IL-4 plus anti-IL-12 to generate Th1- and Th2-polarized cultures respectively. Cultures were exposed to the NO donors Spermine-nonoate (Sper) and DPTA-nonoate to study NO-induced apoptosis. We found that NO preferentially induced apoptosis in Th1-polarized cells as demonstrated by Annexin staining in the presence of 10 microM Sper (70 +/- 16 versus 23 +/- 4.4% in Th2 cells P: < 0.01) and by DioC6 staining (38 +/- 10 versus 11 +/- 5% in Th2 cells, P: < 0.01). The mechanism of NO-induced apoptosis in Th1/Th2-polarized cells was distinct from AICD and Fas-induced apoptosis. Differential sensitivity between Th1- and Th2-polarized cultures originated at the level of intracellular glutathione (GSH) metabolism. GSH levels were higher in Th2 cells (1.6 +/- 0.2-fold Th1, P: < 0.01). High intracellular GSH in Th2-polarized cells did not account for reduced susceptibility to NO per se, since the inhibition of gamma-glutamyltrans-peptidase (gamma-GT), which is involved in GSH import, sensitized Th2 cells to NO-induced apoptosis without GSH depletion. Therefore, higher activity of gamma-GT in Th2 cells (2.1 +/- 0.4-fold Th1, P: < 0.001) specifically protects Th2 cells against NO-induced apoptosis. Preferential NO-induced elimination of human Th1 cells at sites of inflammation may thus select Th2 cells and contribute to immune deviation.

Peroxynitrite (ONOO−) the highly reactive coupling product of nitric oxide and superoxide, has been implicated in the pathogenesis of an increasing number of (inflammatory) diseases. At present, however, selective peroxynitrite antagonizing agents with therapeutic potential are not available. Therefore, the NADPH‐oxidase inhibitor apocynin (4‐hydroxy‐3‐methoxy‐acetophenone) was tested for its ability to inhibit peroxynitrite formation in vitroThe murine macrophage cell‐line J774A.1, stimulated with IFNγ/LPS, was used as a model. Conversion of 123‐dihydrorhodamine (123‐DHR) to its oxidation product 123‐rhodamine was used to measure peroxynitrite production.Stimulated peroxynitrite formation could be completely inhibited by apocynin, by the superoxide scavenger TEMPO as well as by the nitric oxide synthase inhibitor aminoguanidine. Apocynin and aminoguanidine specifically inhibited superoxide and nitric oxide formation respectively as confirmed by measuring lucigenin enhanced chemiluminescence and nitrite accumulation.It is concluded that J774A.1 macrophages produce significant amounts of peroxynitrite, which is associated with nitric oxide production and NADPH‐oxidase dependent superoxide formation. The NADPH‐oxidase inhibitor apocynin proved to be a potent inhibitor of both superoxide and peroxynitrite formation by macrophages, which may be of future therapeutic significance in a wide range of inflammatory disorders.

Atopy can express itself as asthma, rhinitis and eczema. The presence of atopy can be assessed by increased levels of total serum IgE and specific IgE to common allergens, skin test positivity and increased numbers of peripheral blood eosinophils. Genetic studies indicate that multiple genes are involved in the pathogenesis of atopy and that different genes regulate the presence of increased levels of serum total IgE and specific IgE. Linkage of these traits to chromosomal regions likely to contain atopic susceptibility genes has been replicated in several studies. Genome-wide screens have identified several new chromosomal locations that are likely to contain atopic genes. These regions also contain candidate genes. Moreover, the available literature suggests that multiple, yet different genes may be involved in the translation of atopy to a distinct clinical phenotype. We anticipate that understanding of the genetic basis of atopy will lead to new therapeutic interventions and early diagnosis.

1. To determine whether an autonomic nervous system imbalance might underlie the nocturnal dyspnoea in patients with chronic airflow obstruction (CAO), we determined FEV1, sinus arrhythmia gap (SA gap), heart rate and urinary adrenaline and noradrenaline excretion every 4 h over 24 h. Measurements were performed in eight non-allergic patients with CAO and eight age- and sex-matched normal controls. 2. The amplitude of the circadian changes in FEV1 in patients and controls was 27 ± 2% and 7 ± 1% respectively (P < 0.001). 3. Both an increased SA gap and a decreased heart rate are features of increased vagal activity. This vagal activity was significantly increased in patients, compared with normal controls (difference P < 0.01), the difference being maximal at night. This increased activity might contribute to a bronchial obstruction in these patients. 4. Urinary adrenaline excretion was significantly higher by day than by night in both patients and normal controls (P < 0.01). The urinary levels of adrenaline in the patients were significantly decreased at all hours of observation as compared with levels in normal controls (P < 0.05). 5. Urinary noradrenaline levels were significantly lower in patients as compared with normal subjects (P < 0.01), and lower by night than by day. 6. Urinary histamine and Nτ-methylhistamine excretion were in the normal range in each individual. Urinary levels, however, were significantly higher in patients at all hours of observation (P < 0.05). No circadian rhythm was shown. Plasma cortisol levels showed a normal circadian variation, similar in patients and normal subjects. 7. Bronchial constriction in patients with CAO may be explained by an autonomic nervous system imbalance. Arguments favouring this hypothesis were the findings that CAO patients, in contrast with normal controls, showed lower urinary adrenaline and noradrenaline excretion throughout with a fall at night, and a higher vagal tone with an increase at night. Moreover, a higher histamine and Nτ-methylhistamine excretion both day and night existed in the patient group. A combination of these factors may lead to the nocturnal dyspnoea in patients with CAO.

In eight non-allergic patients with chronic airflow obstruction (CAO) and eight age and sex matched, healthy control subjects the circadian variation in circulatory lymphocyte count was studied in relation to serum Cortisol and urinary epinephrine levels. In addition, we investigated the effect of the beta-adrenergic agent terbutaline on the lymphocyte count in two ways: as a long-term effect after 8 days of oral slow-release terbutaline with constant diurnal and nocturnal serum levels in patients, and as a short-term effect by a constant rate infusion of 0.2μμg/min over 4hr in normals. Both patients and controls showed similar circadian patterns of urinary epinephrine excretion and lymphocyte counts. Patients with CAO, however, had significantly lower epinephrine levels and significantly higher lymphocyte counts at all hours of observation (every 4 hr from 0800 to 0800 hr the next day), as compared with normal controls. After 8 days of slow-release terbutaline the lymphocyte count in the patient group decreased to levels not significantly different from that of normals. The circadian rhythm of the lymphocytes, however, persisted under terbutaline therapy. No correlation existed between the lymphocyte count modulating factor, serum Cortisol and the lymphocyte count over 24 hr. On placebo infusion in the control persons an increase of lymphocytes over 4hr occurred, as a consequence of circadian rhythmicity. On terbutaline infusion a significant increase of lymphocytes after 1hr was follwed by a decrease to levels significantly below those on the placebo day. The same pattern was found in the leucocyte count. From this study it is concluded that beta-adrenergic stimulation corrects the relative lymphocytosis to counts comparable with normals. Other coinciding factors must regulate, however, the circadian rhythmicity.

Eight male patients with partly reversible airflow obstruction, who had a diurnal variation in peak expiratory flow rate (PEFR) of more than 20% were treated with placebo and slow-release terbutaline tablets (5 mg at 08.00 hours and 10 mg at 20.00 hours) for 8 days. On Day 8 of each period, PEFR and serum terbutaline were measured at 4 and 2-h intervals, respectively. PEFR on the terbutaline day showed a significant increase at 08.00, 12.00, 24.00, 04.00 and 08.00 hours as compared to the placebo day. Slow-release terbutaline prevented early morning dyspnoea. The serum concentration was 3.3 ng/ml during the day and 3.5 ng/ml during the night. During terbutaline therapy the patients reported fewer complaints than during the placebo period. It was concluded that slow-release terbutaline tablets are suitable for twice daily treatment.

Genetics studies of total serum IgE levels were performed since high IgE levels correlate with clinical expression of allergy and asthma. Families ascertained through a parent with asthma were genotyped for markers on 5q where there are multiple candidate genes that may influence the control of IgE and inflammation. Evidence for linkage of the IgE phenotype to 5q was obtained by both sib-pair and lod score analysis with evidence for recessive inheritance of high IgE levels from segregation analysis. These findings represent a major step in mapping genes important in the regulation of allergic responses and the pathogenesis of asthma. Copyright 1994, 1999 Academic Press