Comparison of the effects of epithelium removal and of an enkephalinase inhibitor on the neurokinin-induced contractions of guinea-pig isolated trachea.

1. The influence of epithelium removal and/or thiorphan on the effects of neurokinins (substance P (SP), neurokinin A (NKA), neurokinin B (NKB)) and related peptides on airway contractility was investigated on the guinea-pig isolated trachea. 2. Removing the tracheal epithelium significantly enhanced the sensitivity but not the maximum contractile responses to the peptides. 3. After removal of the epithelial layer, the shifts to the left of the log concentration response curves were greater for SP and SP-OMe (1.62 and 1.94 log units, respectively) than for two SP analogues substituted in position 9 namely [Pro9]SP sulfone and [beta-Ala4, Sar9]SP(4-11) sulfone (0.66 and 0.68 log units, respectively). The leftward shifts for compounds related to NKA or NKB lay between 0.58 and 0.73 log units. 4. The leftward shifts of the log concentration-response curves for SP, SP-OMe, [Pro9]SP sulfone, [beta-Ala4, Sar9]SP(4-11) sulfone and NKA were of similar magnitude after removal of the epithelium or after pretreatment with thiorphan (10(-5) M), an enkephalinase inhibitor, in the presence of epithelium. No significant additional shift of the curves to the left was observed with thiorphan plus epithelium removal. 5. The results obtained with the selective agonists for each of the three classes of neurokinin receptor (i.e NK1, NK2, NK3) suggest that the guinea-pig trachea contains receptors for SP and NKA but few if any for NKB. 6. It was concluded that neurokinins and related peptides (especially SP and analogues not substituted in position 9) are degraded by enkephalinase mainly located in the tracheal epithelium and that the addition of thiorphan or epithelium removal results in an inhibition or loss of enkephalinase activity, thereby increasing similarly the potencies of these peptides. It was, therefore, suggested that the supersensitivity to neurokinins produced by epithelium removal was due neither to the elimination of a permeability barrier nor to reduced production of a relaxant factor, but mainly to reduced peptide degradation.

Evidence that the histamine sensitivity and responsiveness of guinea-pig isolated trachea are modulated by epithelial prostaglandin E2 production.

1. Guinea-pig isolated tracheal preparations in which the epithelium had been removed exhibited a greater contractile response to histamine (intact: 1.91 +/- 0.12 g; n = 6 and rubbed: 2.76 +/- 0.15 g; n = 11; P less than 0.001). The histamine sensitivity (pD2 value) of these preparations was also significantly greater (intact: 4.80 +/- 0.04 and rubbed: 5.40 +/- 0.08; P less than 0.01). 2. Indomethacin suppressed the basal tone of both intact and rubbed preparations but was more effective in the former tissues (intact: -0.70 +/- 0.14 g; n = 22 and rubbed: -0.17 +/- 0.05 g; n = 12; P less than 0.02). 3. Arachidonic acid (AA; 10 microM) suppressed the basal tone of intact tissues but contracted such preparations following indomethacin treatment (1.7 microM; 30 min). However, in rubbed tissues AA (10 microM) induced a contraction which was attenuated following indomethacin treatment. 4. Prostaglandin E2 (PGE2; 0.01 and 0.1 microM) suppressed the basal tone of intact preparations and always evoked contraction of rubbed tissues. Following indomethacin treatment PGE2 (0.01 and 0.1 microM) generally evoked spasm of intact and rubbed tissues while at higher concentrations (1 microM) relaxant effects were observed. 5. Removal of the epithelium did not alter the relaxant effect of PGE2 (pD2 value) on histamine (50 microM)-contracted tissues (intact: 6.86 +/- 0.08 and rubbed: 7.10 +/- 0.3; n = 4; P greater than 0.1). 6. In rubbed preparations treated with indomethacin, PGE2 (0.01 and 0.1 microM) evoked spasm. However, when added to preparations contracted with 5 microM histamine, PGE2 always caused relaxation. 7. The release of immunoreactive PGE2 by rubbed preparations during histamine and/or AA stimulation was significantly less than that produced by intact stimulated tissues. 8. Exogenous PGE2 (0.01-1 microM) decreased the maximal response and sensitivity of rubbed tracheal preparations to histamine. 9. These results suggest that release of an epithelial derived cyclo-oxygenase product, namely PGE2, may regulate basal tone, histamine response and sensitivity of the guinea-pig isolated trachea.

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.

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.

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.

Broncho-alveolar lavage in sarcoidosis. Correlation between alveolar lymphocytosis and clinical data.

Bronchoalveolar lavages (BAL) were performed in patients with pulmonary sarcoidosis and in normal subjects. In both smoking and nonsmoking sarcoid patients, the proportion and number of lymphocytes were significantly increased compared to corresponding controls (p less than 0.001 in each cases). BAL lymphocytes were identified as T lymphocytes (88 +/- 9% formed E rosettes). Neither the radiological stage, nor the duration of disease are related to the lymphocyte number. However, alveolar lymphocytosis is significantly correlated with clinical pattern (p less than 0.02) and with clinical extrathoracic dissemination (p less than 0.001). Black patients have significantly more disseminated disease than Whites (p less than 0.001). The lymphocytosis of the bronchoalveolar space is associated with the presence of granulomas in bronchial biopsies (p less than 0.005). For clinical purposes, the results of BAL were helpful in determining the evolutivity of the disease, particularly progression to stage III. Together with a high lymphocyte count, a significant increase of all the polymorphonuclear leukocytes (PMNL) was found in stage III (4.0 +/- 4.6 X 10(4) PMNL/ml, p less than 0.001) compared to earlier stages (respectively 0.6 +/- 0.5 X 10(4), 0.7 +/- 0.9 X 10(4) and 0.7 +/- 0.9 X 10(4) PMNL/ml for stages I, IIA and IIB). BAL may also be used to follow up sarcoid patients. Repeated BAL were performed in 23 patients. No modification in alveolar lymphocytosis is found in patients with steady state disease, but, in healed patients the lymphocyte number returns to normal.

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.

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.

[Pharmacokinetic interactions of macrolides and theophylline]. / Les interactions pharmacocinétiques entre les macrolides et la théophylline.

Interaction between macrolides and theophylline has given rise to numerous studies which are reviewed in this paper. The results of these studies are often conflicting. When such interactions occur, the question is whether they have clinical significance.

[The nonadrenergic, noncholinergic neuropeptide system and asthma]. / Système non adrénergique non cholinergique, neuropeptides et asthme.

An understanding of the non adrenergic non cholinergic nervous system and its implication in the pathogenesis of asthma would benefit by the identification and localisation of the numerous natural bioactive peptides at the pulmonary level. In the past few years two components of the non adrenergic non cholinergic nervous system have been characterised. A bronchodilator component which would be mediated by "vaso-active intestinal peptide" (VIP) and the "peptide histidine methionine" (PHM). A broncho-constrictor component which would be mediated by the neurokinins (substance P (SP), neurokinin A (NKA) and the "calcitonin gene related peptide" (CGRP)). These neuropeptides, in vitro as well as in vivo, have effects which are not limited to the regulation of bronchial smooth muscle tone. In effect, they may intervene in the regulation of vascular tone, in the production of mucous and in the expression of immediate hypersensitivity reactions at pulmonary level. Several neuropeptides are present or co-exist with classical neurotransmitter in the afferent nerve endings of the pulmonary efferents. This co-existence of several neurotransmitters in the same nervous fibres raised the questions as to their interactions at the pre or post synaptic level. The implication of these neuropeptides in the pathogenesis of asthma rests on numerous experimental arguments. This recent aspect in the pathophysiology of asthma allows us to hope for new therapeutic approaches.

[Exercise-induced asthma]. / L'asthme post-exercice.

Exercise-induced asthma only differs from common asthma in its causative factor. It is a typical asthmatic attack which follows a strenuous and continuous physical exercise lasting 5 to 10 minutes, most often in cold and dry weather. The prevalence of exercise-induced asthma has not yet been firmly established; its pathophysiological mechanisms are still debated, and the respective roles of heat and water losses by the airways are not clearly defined. However, the influence of the type of exercise as a precipitating factor of exercise-induced asthma is now well-known. All things being equal, swimming generates less asthma than running and cycling. This enables the subjects to be directed towards the most suitable sports and encouraged to improve their physical fitness. Drug treatment of exercise-induced asthma must preferentially be preventive; it relies on cromoglycate and beta-2 adrenergic agonists, the latter being also capable of treating acute exercise-induced bronchial obstruction. Education of the patients and their family is also important.

[Mechanism of action and effects of corticoids in asthma]. / Mécanismes d'action et effets des corticoïdes dans l'asthme.

The value of oral or inhaled glucocorticoids (GCS) in asthma is well recognized. Their use has remained empirical for a long time. However, some progress has been achieved recently in the understanding of their general mode of action and of their bronchial effects suggesting that in the near future ther may be some new therapeutic perspectives. The fundamental action of GCS involves a close intracellular interaction between the specific glucocorticoid hormone receptor and the cellular genome which results in the activation of the genes coding the proteins responsible for the phenotypic response of the cell and thus for their biological action. The place of the extra-genomic mechanisms remains ill understood. The immunomodulating action of GCS is difficult to dissociate from their anti-inflammatory and anti-allergic effects which seem to predominate in asthma. They inhibit all stages of the inflammatory reaction in acting on the key mediators of the inflammatory response, the pharmacologically active lipids (LPA: prostaglandins, leukotrienes, PAF-acether) which are a result of the catabolism of arachidonic acid which occurs during the course of membrane activation. The phospholipid A2 (PLA2), a membrane enzyme responsible for the splitting of the phospholipids in the presence of calcium and leading to the liberation of LPA is the driving force of the reaction in such a way that the products of the nuclear activation subsequently reactivated. GCS is considered as a natural modulator of inflammation, inducing the synthesis of lipocortin, an inhibitory protein of PLA2, which explains the blockage in the generation of LPA and thus the inflammatory reaction. The regulation of the activity of these or of the lipocortin seems to lead to the intervention of the phosphorylation. But numerous questions remain concerning the precise action of PLO2, the existence of endogenous lipocortin, their secretion and their extra-cellular action. In spite of these unknown facts it is not impossible to envisage a clinical potential for lipocortin, once sequenced and produced, when the pharmacological and immunological problems have been surmounted. In asthma the effect of GCS essentially involve: the inhibition of all the bronchial components of inflammation: the synthesis, liberation and peripheral action of the mediators; the oedema and mucous congestion.(ABSTRACT TRUNCATED AT 400 WORDS)

[Human Pasteurella multocida infections. Value of serological diagnosis]. / Les infections humaines à Pasteurella multocida. Intérêt du diagnostic sérologique.

In five human cases of Pasteurella multocida infection, high titres of specific antibodies were found by indirect haemagglutination (capsular antigens) and agglutination (somatic antigens). The specificity of the antibodies fitted with the serotypes of the isolated strains (three A 3 and two A 7). Subsequent changes in antibody titres in human beings were similar to those observed in animals. The risk of this animal-acquired infection being probably underestimated in medical practice, the usefulness of these tests in human beings is discussed.

[Aerosol therapy in asthma]. / Aérosolthérapie dans l'asthme.

Today there is a general use of aerosols in the treatment of asthma. To understand their importance it is necessary to know the make-up of an aerosol, physical and chemical factors as well as anatomical factors that influence its deposition and clearance in the tracheo-bronchial tree. In the therapy of asthma, small, easy-to-handle and reliable inhalers are prescribed. Other methods of administering these drugs by inhalation are available: these include nebulisation of the active substance in a liquid form and inhalation of the drug in a powder form. Their efficacy and the rareness of side effects (owing to the fact of minimal systemic absorption) makes them the preferred form of treatment of crises as well as for basic treatment. Nevertheless, to obtain the best therapeutic results the inhalation technique of the aerosol should be correct and some practical improvements are envisaged to alleviate any disadvantages: mixing chambers, mouth pieces, etc. Several drugs are commercially available in aerosol form (beta-agonists, atropine-like drugs, corticosteroids and chromones) which have a place both in the treatment of crises and in the basic treatment of asthma.

[Evaluation of the medical costs of asthma in adults during a l-year follow-up in a hospital environment]. / Evaluation du coût médical de l'asthme de l'adulte au cours d'une année de surveillance en milieu hospitalier.

The medical cost of asthma is difficult to measure because this syndrome is generally studied in amongst a large group of patients with chronic respiratory disease. The aim of this study was to assess the theoretical cost of the medical treatment of asthma in a group of young adults who are free from any other disease; the study lasted for one year of follow up and the treatment was given in the public hospital service. Four particular situations are identified corresponding to four stages of severity of the disease and each of these stages was given a treatment selected as the usual therapeutic regime given in a respiratory service in a public hospital. The first stage was to suit patients suffering from quarterly paroxysmal crises which tended to resolve quickly after a few days of treatment. The second stage was more severe involving patients suffering from monthly paroxysmal attacks and for whom maintenance treatment was necessary. The third stage was for those with unstable asthma with twice monthly asthmatic crises, frequent hospitalisation and continuous treatment between the attacks. In the fourth stage the patients were suffering from continuous dyspnoea which required inpatient hospital care and also intensive care. In all these cases the asthmatic disorder is burdensome both for the patient and for society, a fact which should be appreciated both by doctors and by decision makers in public health. In the average or mild cases the essential annual costs are made up of the cost of diagnosis and follow up.(ABSTRACT TRUNCATED AT 250 WORDS)

[Sulfidopeptide leukotrienes and asthma]. / Les sulfidopeptides leucotriènes et l'asthme.

The role of sulfidopeptide leukotrienes in asthma alone or in association with other mediators is still debated. Sulfidopeptide leukotrienes (s-LT) C4, D4 and E4 are 5-lipoxygenase derivatives of membrane arachidonic acid. All s-LT contract bronchial smooth muscle in vitro and provoke an acute bronchial obstruction in vivo in both healthy and asthmatic subjects. Numerous cells, including mast cells, alveolar macrophages, polynuclear basophils and eosinophils, are capable of secreting s-LT following such diverse stimuli as allergen exposure, platelet activating factor and calcium ionophore A 23187. In addition to constricting bronchial smooth muscle, s-LT promote the occurrence of mucosal oedema increase micro-vascular permeability in the bronchial wall, and cause hypersecretion of mucus by tracheo-bronchial glands. These effects lead to worsening of airways obstruction. s-LT increase non specific bronchial hyper-responsiveness. Clinical trials aiming to test the efficacy of new anti-leukotrienes are currently under way. In general these products have a real antagonistic effect on exogenous s-LT. Their efficacy vis-a-vis other types of stimulus such as allergens, histamine and exercise does not seem to be constant and depends largely on the composition and perhaps the route of administration (inhaled versus oral). The contribution of s-LT as part of the therapeutic arsenal for the long term treatment of asthma remains to be established.

[Smoking among nursing students]. / Le tabagisme chez les élèves infirmières.

The aim of this work is to study smoking habits in young adults in a particularly sensitive environment. The data were collected in 28 nursing schools of the Public Hospital System in Paris by means of anonymous self-administered questionnaire. The questions focused on smoking habits, knowledge of risks and student attitudes. The 5,598 respondents (mean age of 22.6 years) were 89 per cent female. The results showed a high prevalence of current smoking (44%) especially amongst the younger students. Students preferred brands with a medium range tar level. Most of the students knew the smoking risk, agreed with the policy of prohibiting smoking in the hospital and thought that it is the role of nurses to counsel patients to stop smoking, but only one third hold a positive view of this role.

[Surgically-treated small size non-small cell bronchopulmonary cancers without adenopathies (T1NO). 5-year survival and site of recurrences]. / Cancers bronchopulmonaires "non à petites cellules", de petite taille et sans adénopathie (T1N0) opérés. Survie à 5 ans et siège des rechutes.

From October, 1976 to February, 1982, 48 patients with T1N0 non-small cell bronchopulmonary carcinoma were operated upon at the Laennec Hospital, Paris. Their characteristics were: mean age 57 years (range: 43-80 years); sex ratio 23; type of surgery: 35 lobectomies, 11 pneumonectomies, 2 bilobectomies; histology: 30 epidermoid carcinomas, 15 adenocarcinomas, 3 bronchoalveolar carcinomas. On 1st January, 1983, 10 patients had relapsed after a mean complete remission period of 20 months (range: 2-29 months); 5 only had a local relapse. The actuarial probability of relapse at 5 years is 45%. Twelve patients died after a median survival of 21 months (range: 0-44 months). Of these, 3 died post-operatively, 8 after relapse and 1 of infarction during a first complete remission. Most relapses involved the mediastinum (50%) and the brain (30%). As the preventive role of mediastinal and cerebral irradiation has now been demonstrated in more extensive forms of non-small cell carcinomas, such irradiations would be justified in the T1N0 forms.

[Emergency treatment of severe hemoptysis by embolization of systemic arteries]. / Traitement en urgence des hémoptysies graves par embolisation des artères systémiques.

Over a 6-year period 23 patients with massive haemoptysis were treated at the Hôpital Tenon, Paris. Eighteen of these, usually considered "non-surgical" cases, underwent emergency embolization of the bronchial artery (B.A.E.). The immediate outcome was favourable in 14 patients; 4 died of early recurrence. B.A.E. therefore appears to be a valuable treatment of massive haemoptysis in "non-surgical" patients or in patients awaiting transfer to a thoracic surgery unit. However, because of the failure rate, B.A.E. cannot compete with thoracic surgery in its classical indications, and its effectiveness and safety should be compared with those of balloon catheter endobronchial tamponade in "non-surgical" patients.

[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.