The effect of intravenous phenylephrine on airway calibre in asthma.

Tracheobronchial vasoconstriction and subsequent reduction of airway wall thickness due to the alpha 1-agonist methoxamine, might be responsible for prevention of exercise-induced asthma, and reduction of bronchial hyperresponsiveness to methacholine increase in exercise performance in patients with impaired left ventricular function. Since bronchial wall oedema plays an important role in asthma, we have now investigated the bronchial response to the intravenously administered alpha 1-agonist, phenylephrine, in asthma of various severity. Increasing noncumulative intravenous phenylephrine doses (100 to 600 micrograms) were injected in 18 asthmatic subjects (three groups: mild asthma, mild asthma with recent acute attack, severe obstructive asthma) and in 11 control subjects. Changes in specific airways resistance (sRaw) on phenylephrine were linearly related to the dose administered in 16 out of 18 asthmatic subjects, and in only 3 out of 11 control subjects. In the asthmatic subjects, sRaw increased in 10 patients whose asthma was mild, or bronchial obstruction mild to moderate, and decreased in the remaining 8 asthmatic subjects with more severe disease or with a higher degree of bronchial obstruction. Changes in forced expiratory volume in one second (FEV1) were consistent with those of sRaw. In the five asthmatic subjects who underwent the protocol twice, results were reproducible. There was no difference in the responses of heart rate between the three groups of asthmatic subjects. It is likely that phenylephrine acts both via airway smooth muscle contraction, an effect which might predominate in mild asthma, and via mucosal vasoconstriction, which might overcome the effect on smooth muscle in more severe asthma with bronchial wall oedema.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the severity of asthma by an expert system. Description and evaluation.

Asthmaexpert, an expert system (ES), was produced at the special request of several clinicians in order to better understand the medical decisions made clinical experts in managing an asthmatic patient. We describe and evaluate this knowledge base, focusing mainly on assessment of the severity of asthma. After compiling data from a patient, Asthmaexpert assesses the severity of the disease and identifies the trigger factors involved, suggests any further investigations that may be required, and offers a treatment strategy. Implemented with Nexpert and Hypercard, it runs on a MacIntosh personal computer. The validation stage involved eight clinical experts who provided 20 case report forms (CRF) with their conclusions about management of asthma. The CRF were then programmed into the ES, which provided its own conclusions about the same subjects. Afterward, all the experts evaluated the conclusions given by ES or by their colleagues in a double-blind manner. One hundred twenty-seven CRF were available. The reliability of the experts' opinions was good, with a substantial consensus between them when assessing severity scores (kappa = 0.27 to 0.54). There was no difference in concordance of opinions on severity scores either between the experts who designed the system and ES or between the other experts and ES (weighted kappa = 0.72 and 0.69, respectively). Experts judged that the severity scores given by ES were as good as those proposed by their colleagues, and that the overall conclusions given by ES were as good as or better than those given by their colleagues. The conclusions drawn by ES were given a good rating.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pulmonary lymphangiomyomatosis. Long-term benefit of anti-estrogen treatments remains uncertain]. / Lymphangiomyomatose pulmonaire. Le bénéfice des traitements anti-oestrogènes reste incertain à long terme.

Lymphangiomyomatosis is a rare disease which affects young women of childbearing age. Ten women with pulmonary lymphangiomyomatosis were treated with antiestrogen therapy from 3 to 9 years (mean time of treatment: 5.3 years). Efficacy of treatment was evaluated by clinical, radiological, pulmonary function testing response as well as the overall long-term outcome. Four patients died of respiratory failure after 3, 5, 5 and 9 years of treatment. Of the 6 patients remaining alive, respiratory function deteriorated in 4 cases after a transient period of mild improvement lasting 3 years in 2 cases. Two patients appeared stable after 3 and 7 years of treatment. Without a control group, although a longer time of survival along these last years, it seems difficult to impute this benefit to the sole antiestrogen treatment and the overall long term prognosis of the disease remains really uncertain.

Activation of an epithelial neurokinin NK-1 receptor induces relaxation of rat trachea through release of prostaglandin E2.

We studied the type of neurokinin (NK) receptor involved in the epithelium-dependent substance P (SP)-induced relaxation of rat trachea precontracted with serotonin (5-HT). We first compared the relaxant effects of different agonists to the three NK receptors on rat trachea in the presence (E+) and absence (E-) of the epithelium. The three agonists to the NK-1 receptor, SP, SP-O-methylester and [beta Ala4, Sar9, Met(O2)] SP(4-11), at a concentration of 1 microM induced a relaxation of 40 +/- 5, 33 +/- 4 and 31 +/- 6%, respectively in E+ segments. They had weak and nonsignificant effects in E- segments. In addition, (+/-)CP-96,345 (1 microM), the NK-1-selective non-peptide antagonist, inhibited the SP-induced relaxation by 45%. Conversely, the three NK-2 receptor agonists, NKA, NKA(4-10) and [Nle10]NKA(4-10), and the two NK-3 receptor agonists, neurokinin B (NKB) and [MePhe7]NKB(4-10), had no effect on E+ or E- tracheal segments. The N-terminal SP fragment SP(1-9) was also inactive. These results suggest that SP-induced relaxation is mediated through activation of epithelial NK-1 receptors. Preincubation with the cyclooxygenase inhibitor, indomethacin (2.8 microM), abrogated the relaxant effect of the three NK-1 receptor agonists on E+ tracheas. We measured in additional experiments prostaglandin E2 (PGE2), PGF2 alpha, 6-keto PGF1 alpha and thromboxane B2. SP (1 microM) induced a 6.1-fold increase in PGE2 production (from 13 pg after 5-HT to 78 pg) in E+ segments, whereas only a 1.5-fold increase occurred in E- preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary lymphangiomyomatosis. Follow-up and long-term outcome with antiestrogen therapy; a report of eight cases.

Lymphangiomyomatosis is a rare disease which affects young women of childbearing age. Eight women with pulmonary LAM were treated with antiestrogen therapy and were monitored by blood estrogen measurements along with clinical hypoestrogenic symptoms. Treatment ranged from three to nine years. The response to therapy was evaluated by the clinical course, chest x-ray films, pulmonary function tests and overall long-term outcome. Three patients died of respiratory failure after three, five and nine years of treatment. Of the five patients remaining alive, respiratory function deteriorated in four cases, after a transient period of mild improvement lasting three years in two cases. The last patient appeared stable after three years of follow-up. Time course ranged from 4 to 17 years. However, without a control group, we cannot determine whether or not the apparent improvement of the natural time course was due to the hormonal treatment.

Relationship between spontaneous dyspnoea and lability of airway obstruction in asthma.

1. As marked lability of bronchial obstruction is a risk factor for asthma severity, it may influence dyspnoea, the most common subjective complaint in asthma. We therefore studied the relationship between spontaneous dyspnoea and the degree of bronchial lability, as assessed by the daily variability in peak expiratory flow rate and the bronchial responsiveness to either carbachol or salbutamol, in 33 stable symptomatic asthmatic patients. 2. Three times daily, for 10 consecutive days, the patients rated the intensity of their dyspnoea on a visual analogue scale and immediately afterwards recorded their peak expiratory flow rate. Within the next 5 days, we determined the bronchial response by measuring the forced expiratory volume in 1 s and the specific resistance of airways to either carbachol or salbutamol according to baseline airway obstruction. 3. We characterized dyspnoea for each patient by using two parameters: (1) the relationship with underlying airway obstruction, as assessed by the correlation coefficient r between dyspnoea scores and corresponding values of peak expiratory flow rate (r DSc-PEFR), and (2) the intensity, as assessed by the mean visual analogue scale dyspnoea score adjusted for comparable airway obstruction. Bronchial lability was characterized by (1) variability in mean daily peak expiratory flow rate and (2) bronchial responsiveness to either carbachol (as assessed by the threshold dose and the slope of the dose-response curve) or salbutamol (as assessed by the threshold dose and maximal response). We assessed the relationship between dyspnoea and bronchial lability by correlating each of their respective characteristics. 4. We found large inter-subject differences in both characteristics of dyspnoea.(ABSTRACT TRUNCATED AT 250 WORDS)

An international clinical trial on the efficacy and safety of roxithromycin in 40,000 patients with acute community-acquired respiratory tract infections.

An ongoing eight-country study is being conducted in an unprecedented number of general practice patients with acute upper and lower respiratory tract infections to compare the efficacy and tolerance of roxithromycin 150 mg b.i.d. for 7-14 days with the data acquired in the prelaunch studies of these same parameters. The target population is 40,000 (to be achieved by the end of 1991) and we report the interim results from 32,405 patients, 18,020 with upper and 14,385 with lower respiratory tract infections. In acute pharyngitis/tonsillitis sinusitis, and otitis, clinical resolution or improvement has been achieved in 97%, 96%, and 96% of cases, respectively. The figures for bronchitis, exacerbation of chronic bronchitis, and pneumonia are 97%, 94%, and 95%. Side effects have been reported in only 4% of patients to date, 75% consisting of moderate gastrointestinal upsets. Of the patients, 1% withdrew from treatment because of side effects. These interim figures confirm the data from the prelaunch, controlled comparative trials and show roxithromycin to be an appropriate choice of first-line antibiotic therapy in the management of respiratory tract infections in general practice.

Best mode of expression of acute reversibility of airway obstruction in patients with asthma: application to a new beta-2 agonist, RU 42 173.

Lung function tests must distinguish a true drug-induced bronchial response from changes not related to the drug itself, mainly due to intra-individual variability. We compared the variability and ability to detect true drug-induced bronchodilation of 3 modes of expression of the increase in forced expiratory volume in 1 second (delta FEV1) following administration of a 0.25 mg single oral dose of RU 42 173, a new beta 2-agonist. The study was performed in 12 patients with reversible obstructive asthma in a double-blind, crossover, placebo-controlled, randomized manner. The variability of each index was assessed by calculating the coefficient of variation (SD/mean). True drug-induced bronchodilation was assessed by calculating the F value of each index corresponding to the ratio of between-treatment to within-group differences. Three modes of expression of delta FEV1 were compared: delta FEV1 (L) = the absolute increase in FEV1, delta FEV1 (% baseline) and delta FEV1 (% predicted) where delta FEV1 (L) is divided by baseline FEV1 or predicted FEV1, respectively. A statistically significant increase in FEV1 was found up to respectively 3, 2 and 4 hours after dosing when using delta FEV1 (L), delta FEV1 (% baseline) and delta FEV1 (% predicted). The highest F value was obtained for delta FEV1 (% predicted). The coefficient of variation was lower with delta FEV1 (% predicted) than delta FEV1 (L) and delta FEV1 (% baseline). In conclusion, RU 42 173 showed a bronchodilating effect which appears to be clinically relevant. delta FEV1 (% predicted) was to be the least variable and most powerful index and should be preferred to delta FEV1 (L) and even more to delta FEV1 (% baseline) to assess the acute airway response to a bronchodilator drug.

Methods for clinical assessment of expectorants: a critical review.

The purpose of the paper is to discuss some aspects of the methods that are most appropriate for the clinical assessment of new expectorants. Expectorants are drugs devised to help in the removal of bronchial secretions. The evaluation of these drugs is aimed at demonstrating, in controlled trials, their efficacy, safety and, if possible, mechanism of action. Unfortunately, there is no universally accepted assessment technique available. Evaluation of symptoms with the use of self-reported measures is imprecise. Studies of quality of life can assist as a means of assessing the usefulness of this class of drug for patients. Lung function tests evaluate only the possible indirect effects of expectorants; the changes observed are often minor and they do not correlate with other methods of evaluation. Mucociliary clearance studies evaluate bronchial drainage by mucociliary transport and cough. They are a useful pharmacological approach but they cannot replace therapeutic trials. In vitro and ex vivo studies of bronchial secretion, while improving knowledge of the mechanisms of bronchial secretion, fail to predict the modifications of bronchial drainage produced in vivo by cough or mucociliary transport. To be considered efficient, expectorants should not only ease the removal of bronchial secretions, but also improve the patient's condition for the duration of treatment.

High-dose beclomethasone: oral steroid-sparing effect in severe asthmatic patients.

One hundred and twenty four patients with severe asthma requiring maintenance treatment with oral corticosteroids were included in a multicentre, double-blind, randomized study comparing the effects of inhaled beclomethasone dipropionate (BDP) (250 micrograms.puff-1), beginning with 1,000 micrograms daily, vs placebo (P). Pulmonary function was assessed and dosage of prednisone and BDP (or P) were adjusted every 15 days according to a clinical score. Our results showed, after 3 months: 1) A greater drop-out rate in the P group than in the BDP group (36 vs 6%, respectively, p less than 0.01); 2) A total weaning from prednisone in 76% of patients in the BDP group (mean BDP dosage = 1,270 +/- 340 micrograms.day-1, mean +/- SD), vs 34% in the P group (p less than 0.001). The mean daily dosage of prednisone was reduced from 17 +/- 7.5 mg to 3.1 +/- 7.4 mg in the BDP group vs 15.6 +/- 7.7 mg to 9.1 +/- 9.4 mg in the P group (p less than 0.001) without any relationship between the steroid-sparing effect and the initial dosage of prednisone; 3) Mean change in forced expiratory volume in one second (FEV1) was +7 +/- 21% from the initial value in the BDP group vs -6 +/- 20% in the P group; p less than 0.01. Thus, in patients with severe asthma requiring oral corticosteroids, high-dose BDP has an important oral steroid-sparing effect not related to the initial dosage of oral steroids and allows a better control of airway obstruction than oral corticosteroids alone.

Effects of SK&F 104353, a leukotriene receptor antagonist, on the bronchial responses to histamine in subjects with asthma: a comparative study with terfenadine.

We compared the effects of pretreatment of 800 micrograms of inhaled Smith Kline & French (SK&F) 104353, a leukotriene receptor antagonist, and 120 mg of oral terfenadine on the bronchial responses to inhaled histamine in 12 subjects with asthma. The study took place on 3 different days and was conducted according to a double-blind, crossover, double-dummy, randomized, and placebo-controlled design. There was no difference in baseline and prechallenge FEV1 after placebo, SK&F 104353, and terfenadine administration. The median ratio of the provocative dose causing a 20% fall in FEV1 from baseline (PD20) with terfenadine over PD20 with placebo was 12.36 (range, 3.2 to 30.3; p less than 0.01) and that of PD20 with SK&F 104353 over PD20 with placebo was 1.51 (range, 0.8 to 5.9; not significant). Analysis of individual results demonstrated a shift toward the right of the dose-response curves to histamine with SK&F 104353 compared to that with placebo in three subjects, whereas the active compound did not exhibit any protective effect against histamine in the remaining nine subjects. We conclude that there is a leukotriene component to the bronchial responses to histamine in some, but not all, subjects. This component remains, however, small and does not appear to be clinically important in the population of subjects with asthma that was studied.

Inhibition of human and rabbit platelet activation by Ketotifen.

The effects of Ketotifen and disodium cromoglycate were investigated on human and rabbit platelet activation. Ketotifen inhibited dose-dependently human and rabbit platelet aggregation. The paf-acether pathway was the most markedly influenced by Ketotifen in human and rabbit platelets (IC50 = 38.8 +/- 7.7 microM and 7.2 +/- 4.5 microM respectively) as compared to adenosine diphosphate (IC50 greater than 100 microM and 79 +/- 19 microM) and to arachidonic acid (IC50 greater than 100 microM and 98 +/- 28 microM). Similar concentrations of Ketotifen inhibited the ATP release from human platelets induced by paf-acether. Disodium cromoglycate up to 5 x 10(-4) M did not inhibit platelet aggregation induced by paf-acether, adenosine diphosphate and arachidonic acid.

Long-term management of reversible obstructive airways disease in adults.

The goals of the long-term management of reversible obstructive airways disease (ROAD) are to find the minimum treatment that controls symptoms, allows resumption of normal life, prevents severe attack and death, and controls airflow obstruction. ROADs include asthma, chronic bronchitis, and emphysema. Although the differential diagnosis between these different entities may be difficult, they share the same possibilities of pharmacotherapy, including bronchodilator and antiinflammatory drugs. beta 2-agonists administered via inhaled route produce the best bronchodilator/side effects ratio, provided that the drugs reach the bronchi. This underlines the importance of a proper inhalation technique when using a metered-dose inhaler. In patients with hand-breath coordination problems, powder inhalers or spacer devices are useful to ameliorate the therapeutic efficacy of inhaled drugs. Anticholinergic agents are usually less potent bronchodilators than inhaled beta 2 agonists in asthma, but they may have additive effects when associated with beta 2 agonists. Only a therapeutic trial with peak-flow monitoring can demonstrate the efficacy of anticholinergic drugs in individuals. Theophylline's kinetics are characterized by a narrow therapeutic index with high inter- and intraindividual variabilities. Sodium cromoglycate and nedocromil sodium are antiallergic drugs, the efficacy of which has been demonstrated in controlled studies. Corticosteroids are the most efficient anti-asthma drugs. Inhaled corticosteroid dosing should be tailored to each individual. If inhaled corticosteroid therapy is used in an oral corticosparing attempt, patients should be followed-up during several months. The management of ROAD includes the diagnostic procedures, the identification of triggers and inducers of airways obstruction, the assessment of severity of the disease, and then the treatment and education of the patient. Strategy design to achieve proper use of drugs by patients is discussed.

Inhaled beta adrenergic agonists and inhaled steroids in the treatment of asthma.

In summary, inhaled steroids are the treatment to be preferred for patients requiring maintenance therapy with steroids, since they cause a dramatic fall in sensitivity and reactivity of bronchial response, improve lung function to normal, reduce the diurnal variation in peak expiratory flow rates, and markedly reduce symptoms. Nevertheless they must be given at adequate dosage for a long time, associated with inhaled beta-agonists, and in more severe asthma with short courses of oral steroids.

Chronobiological study of the relationship between dyspnoea and airway obstruction in symptomatic asthmatic subjects.

1. We performed a chronobiological study of the relationship between peak expiratory flow rate (PEFR) and magnitude of dyspnoea in 35 symptomatic asthmatic patients to determine how accurately asthmatic subjects assess spontaneous airway obstruction and whether this accuracy varies throughout the 24 h period and depends on characteristics of the subjects or asthma. 2. At 07.00, 11.00, 15.00, 19.00 and 23.00 hours on 8 consecutive days in their ordinary environment and under their usual drug regimen, the subjects first rated their dyspnoea with a visual analogue scale and immediately after recorded their PEFR. 3. The linear regression coefficients between dyspnoea score and PEFR for the 35 subjects were continuously distributed between -0.93 and +0.21, with most r values ranging from -0.9 to -0.5. The group median r values calculated at each time point showed that strongest correlation between dyspnoea score and PEFR occurred at 7 h. which coincided with the lowest PEFR values. 4. We chose r = -0.7 (r2 = 0.5) as a limit to distinguish good perceivers (-1 less than r less than or equal to -0.7) from bad perceivers of airway obstruction. These two populations differed only by a higher variability of both PEFR and dyspnoea score in good than in bad perceivers, but not for severity, duration or treatment of asthma, absolute value of dyspnoea score, age or sex. 5. Our study quantified an important intra- and between-subject variability in the accuracy of perception of spontaneous airway obstruction in asthmatic subjects which seems to be unrelated to most characteristics of asthma.

Serum thymic hormone thymulin activity is normal in children with asthma.

In asthma, it has been hypothesized that suppressor T-lymphocytes play a protective role and have been reported to be functionally abnormal. Thymic hormone thymulin plays a role in the differentiation of T-lymphocytes and plasmatic thymulin concentration and is related to the functional state of the thymus. To assess the participation of the thymus in the impairment of T-lymphocyte function, we measured plasma thymulin activity in children with allergic asthma (N = 40). The plasma thymulin activity was compared with plasma thymulin activity of children with nonallergic asthma (N = 6), children with atopic dermatitis (N = 9) or allergic rhinitis (N = 7), and in age-matched healthy control children (N = 18) (age range of children studied, 2 to 19 years). Thymulin activity was found within the normal range (1/16 to 1/64) in all control children and in all children with allergic asthma and allergic rhinitis, as well as in all children with intrinsic asthma and atopic dermatitis. Our findings are at variance with the low thymulin activity previously reported in allergic asthma, and we could not explain these discrepancies. (Both studies used the same bioassay, and the population studied did not appear to be different.) T-lymphocyte abnormalities in subjects with asthma must be assessed by other means than measurement of thymic function.