[The contribution of cognitive-behavioural therapies to smoking cessation]. / Apport des thérapies cognitivo-comportementales dans le sevrage tabagique.

INTRODUCTION: Behavioural therapies have been developed on the basis of Pavlov's and Skinner's learning theories. They have recently benefited from advances in the understanding of information handling and the organisation of perceptions of experience. It is for these two reasons that these treatments are called cognitive behaviour therapies (CBT). They have now achieved an important role in the treatment of addictions including tobacco smoking. Currently CBT's are seen as promising because they rely on cognitive restructuring combined with learning of new behaviour while following a process appropriate to the changing dynamic of the smoker. BACKGROUND: They have recently been recognised as of grade A effectiveness by the French Institute of Medical Research and may be recommended to all smokers whose primary intention is to stop. The establishment of a collaborative rapport and a therapeutic attitude are essential. They may be used during the three stages of cessation: preparation, stopping, and the prevention of relapse. A personalised functional analysis provides the patient with a management program using behavioural and, above all, cognitive techniques. The ideal is to combine a pharmacological and an optimised cognitive-behavioural approach. VIEWPOINT: The management of smoking patients has advanced with the understanding of a very complex problem, often associated with anxiety-depressive co-morbidities and other addictions. Tobacco specialists, psychiatrists, cognitive-behavioural therapists and addiction therapists must work together in the future, particularly in respect of research protocols. CONCLUSIONS: Cognitive-behavioural therapy is a useful technique in the personalisation and optimisation of management of the patient, particularly in the prevention of relapse. However, the evaluation of CBT is difficult methodologically and there are few studies evaluating CBT alone. On the other hand, CBT is effective, particularly where there are anxiety or depressive co-morbidities or other addictions that are found more and more frequently during consultations for tobacco smoking.

Use of formoterol dry powder administered for three months via a single-dose inhaler in 1,380 asthmatic patients.

Formoterol is a long-acting beta 2-adrenoceptor agonist available in a single-dose breath-actuated device (Foradil) for asthma treatment. Since efficacy and ease of use are key factors for compliance to therapy, the aim of this study was to assess correct use, efficacy and safety of Foradil in a 3-month, open, uncontrolled, multicenter trial. This study was performed on 1,380 patients with moderate or severe persistent asthma treated with inhaled corticosteroid (age: 48.4 +/- 16.2 years; FEV1: 65.4 +/- 19.4% of normal). During the study, compliance was over 90%. More than 90% of the patients used the inhaler correctly and found it easy or very easy to use. The mean increase in peak expiratory flow rate (PEFR), 30 to 60 min after inhalation, was 52.3 and 36.7 l/min for the morning and the evening respectively (p = 0.0001). This increase was already significant 5 min after inhalation, confirming the fast onset of action of formoterol. Mean predose PEFR and daytime/nocturnal symptom scores improved during the length of the study. Rescue short-acting beta 2-agonist consumption was more than three times reduced. At study completion, formoterol dosage was 12 micrograms and 24 micrograms twice daily for 71.5% and 28.5% of the patients respectively. Physicians judged the overall efficacy as good or very good in 87.1% of the patients, and they estimated the tolerability as very good or good in 92.6%. Drug-related adverse events were similar to those of other beta 2-agonists. In conclusion, this study demonstrated the ease of use of this formoterol single-dose dry powder inhaler, and confirmed the good efficacy and safety profile of this long-acting bronchodilator in asthma.

Inhibitory effect of cetirizine on the bronchial eosinophil recruitment induced by allergen inhalation challenge in allergic patients with asthma.

In patients with asthma there is a recruitment of eosinophils in bronchoalveolar lavage fluid (BALF) after the late asthmatic reaction (LAR). Cetirizine is a selective H1 antagonist that inhibits the eosinophil recruitment induced by allergen in the skin. The aim of this study was to evaluate whether cetirizine was able to inhibit the LAR-induced inflammatory reaction. Twelve allergic asymptomatic subjects with asthma (aged 18 to 58 years) without any treatment were enrolled in the study; FEV1 was greater than 83% predicted in each case. An allergen inhalation-challenge test was performed to assess the presence of an LAR. In a double-blind, randomized, placebo-controlled study, the patients were treated for 8 days with either cetirizine, 15 mg twice a day (six patients, group 1), or placebo (six patients, group 2). On day 8, a second allergen inhalation-challenge test with the same allergen was performed, and BAL was realized 24 hours later; as usual 250 ml of saline was instilled by 50 ml aliquots, and the first recovery was analyzed separately. In each case, the LAR observed after treatment was similar to the first one. In placebo-treated patients, an increased number of cells, mainly eosinophils, was observed in the first recovery of BALF compared with the number in subsequent recoveries. These numbers were significantly higher than numbers observed in cetirizine-treated patients. Cetirizine did not modify significantly the allergen inhalation-challenge test, but it inhibited the recruitment of inflammatory cells, mainly eosinophils.

[Role of beta-2-mimetic agents in the treatment of asthma]. / Place des bêta 2 mimétiques dans le traitement de l'asthme.

Recent modifications of pre existing Beta 2 drugs and new substances with a prolonged bronchodilator effect may improve asthmatic treatment, in term of duration of benefit and compliance to medication. Evaluation of bronchodilation is still debated. When single dose of drug is administered, nycthemeral rhythm, baseline pulmonary function are to be taken in account. In case of long term treatment studies, evaluation of the effects is based upon clinical score, sequential pulmonary function tests, morning and evening peak expiratory flow rates. Risks way be related to be related to beta 2 drugs or concomitant therapy or associated pathology. Indications of dose and route administration are related to asthma severity. Question to state if beta 2 drugs may be considered as prevention treatment. Studies with compounds exhibiting prolonged bronchodilating effect are able to reduce nocturnal asthma, peak flow instability and to improve clinical scores and pulmonary function.

Ambulatory long-term subcutaneous salbutamol infusion in chronic severe asthma.

Although most patients with asthma improve with currently available drugs, there appears to be a subset of patients with asthma resistant to intensive treatment, including large doses of systemic corticosteroids. In 10 patients with asthma difficult to treat, a double-blind, placebo-controlled, crossover study was performed to evaluate whether long-term, continuous subcutaneous infusion of large doses of salbutamol, in addition to steroids, could improve pulmonary function, compared with intermittent nebulization of salbutamol. Four weeks of administration of large doses (greater than 14 mg/day) of beta 2-agonists were well tolerated, elicited a significant decrease of corticosteroid consumption (p less than 0.01), and were associated with an improvement in pulmonary function (p less than 0.01), compared with run in or the placebo administration period. Mean morning and evening peak expiratory flow rates were similar during all periods, and the variability between morning and evening peak expiratory flow rates was only slightly and nonsignificantly reduced during the period when salbutamol was administered subcutaneously. Both nebulized and subcutaneous salbutamol elicited similar metabolic and muscular side effects, but these untoward reactions never caused any patient to stop the treatment. Local infection at the injection site was observed in two of 10 patients with continuous subcutaneous infusion. Tachyphylaxis to beta 2-agonist, as measured by the reversibility of FEV1 to inhaled salbutamol 12 hours after the end of each period, did not occur. In conclusion, large doses of beta 2-agonist administered to patients with severe, chronic, and steroid-dependent asthma were able to improve respiratory function and to decrease corticosteroids requirements.

Characteristics of bronchodilating activity of formoterol.

Formoterol possesses a chemical structure characterized by an NH group attached to the benzene ring and an important side chain. This characteristic may explain its long-lasting effects observed in animal and humans. Formoterol is as active as salbutamol in terms of maximum improvement of FEV1 and its bronchodilating effect is observed at all levels of the bronchial tree.

Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. Systemic reactions during the rush protocol in patients suffering from asthma.

Specific immunotherapy can induce severe systemic reactions (SRs), especially in patients with asthma. It also appears that potent standardized extracts may be more often involved in the generation of SRs than other extracts. Since these SRs may be potentially life threatening, it is desirable to predict their onset. A prospective study was carried out in 125 mite-allergic subjects with asthma ranging in age from 4 to 57 years to assess the incidence of SRs during a rush immunotherapy (RIT) protocol and maintenance injections and to attempt to predict the onset of the SRs. All patients received the same standardized extract of Dermatophagoides pteronyssinus with the same RIT and the same maintenance dose (3000 BU in subjects older than 10 years and 1500 BU in children younger than 10 years). Patients were carefully monitored during the RIT protocol, and possible SRs were followed for up to 2 hours after injections. Patients then received maintenance injections for a mean duration of 18.2 +/- 5.6 months. During maintenance injections, patients were under supervision of a physician for 30 minutes. Within 2 weeks before the RIT, all patients older than 6 years had a pulmonary function test, skin prick test end point with the standardized D. pteronyssinus extract, and RAST. The severity of asthma was examined with the score of Aas. Forty-seven patients had an SR during the RIT protocol: four mild generalized urticaria, 35 asthma exacerbations, and eight anaphylactic shocks. None of the patients had to be admitted to an intensive care unit. Most SRs started within 15 minutes, and none of the SRs started 45 minutes or later after the last injection.(ABSTRACT TRUNCATED AT 250 WORDS)

[Physiopathology of asthma]. / Physiopathologie de l'asthme.

Bronchial asthma is a unique disease; knowledge of the pathophysiology increases rapidly and underlines that is more a syndrome than a disease. Indeed a new definition has been recently proposed: desquamative eosinophilic chronic bronchitis. The airway obstruction, which is responsible for the wheezing breathlessness, is the consequence of a spasm but also an inflammation. After activation of the resident cells in the airways (mast cells, epithelial cells and alveolar macrophages), mediators are released and - in cooperation with the nervous system-recruit inflammatory cells from blood and bone marrow (mainly eosinophils). A kind of vicious circle seems to amplify the initial (allergic or not) event. Desquamation of the epithelium and disposition of collagen on the basement membrane take a quite long time to be cleared after an asthma attack. Mechanisms of repair must be studied in order to improve treatment. Bronchial asthma is not really a disease; indeed a lot of precipitating agents are able to induce and increase bronchial hyperreactivity. Allergy is the most important factor; but environment, hormones and other infectious agents could be quite important in many patients.

Specific immunotherapy with a standardized Dermatophagoides pteronyssinus extract. II. Prediction of efficacy of immunotherapy.

House dust mites of the species Dermatophagoides pteronyssinus (Dpt) represent one of the major allergens inducing asthma. However, a strict allergy to Dpt is not always observed in Dpt-allergic patients, since nonallergic and other allergic triggering factors often coexist. It was suggested that specific immunotherapy with house dust-mite extracts is more effective in children than in adults. A controlled study was undertaken in 215 Dpt-allergic patients with asthma ranging in age from 3 to 72 years (mean +/- SD, 28.2 +/- 10.9 years) to investigate parameters that might predict the efficacy of specific immunotherapy before it is started; 171 patients received a rush immunotherapy protocol with a standardized Dpt extract and, subsequently, maintenance injections with 3000 BU of this extract, and 44 patients served as a control group. Before immunotherapy, all patients had a complete evaluation of the severity of asthma by symptom-medication scores and a pulmonary function test, as well as a study of other triggering factors by checking on seasonal and perennial allergens, sinusitis, and other possible causes, such as aspirin intolerance; 196 patients were investigated between 9 and 12 months after the onset of the survey by means of pulmonary function tests and symptom-medication scores. Medications were adapted according to peak flow rates. It was observed that patients with chronic sinusitis, and/or aspirin intolerance, and/or other perennial allergies did not benefit from specific immunotherapy; therefore, the treatment of a major etiologic factor did not demonstrate improvement in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term therapy with beta-2 mimetics: role of tachyphylaxis]. / Traitement prolongé par bêta-2 mimétiques: place de la tachyphylaxie.

Long-term treatment with beta-2 agonists are said to induce bronchial adrenergic receptor desensitization. Tachyphylaxis is a pharmacological phenomenon that is usually observed with all the drugs and hormones that stimulate receptors. It plays a regulatory role in coupling-decoupling of hormone and receptor. In asthmatics, loss of bronchial responsiveness to a beta-2 adrenergic stimulation may differ from tachyphylaxis, since many factors contribute to the decrease of the response. Penetration of aerosol depends on bronchial obstruction, hypersecretion and inflammatory processes. Aerosols may induce bronchospasm that is related to propellants, the absorption of oral forms beta-2 agonists may exhibit large variation. Few longitudinal or transversal studies to detect the frequency tachyphylaxis in asthmatics have been done, but it has been shown recently that, in a population of asthmatics who were receiving long-term treatment, loss of bronchial response to beta-2 agonists, possibly related to receptor desensitization, was in a range of 10 to 15%.

Effect of long-term treatment with celiprolol on pulmonary function in a group of mild hypertensive asthmatics.

Previous studies have shown that single dose or short-term administration of celiprolol does not impair pulmonary function in patients with asthma. The long-term effects of celiprolol and chlorthalidone on respiratory function in mild hypertensive asthmatic patients were compared. Following a 1-month placebo washout period, five patients were randomized to 3 months of treatment with celiprolol, and four patients were treated with chlorthalidone. This double-blind study was followed by a 12-month open trial in 13 asthmatics. Forced expiratory volume at the first second of expiration (FEV1) remained unchanged throughout the 12-month treatment period. This finding is of interest since a spontaneous decrease in FEV1 of 20 ml/year has been observed in recent surveys of asthmatic patients. No changes in peak expiratory flow rate or maximum expiratory flow at 50% of vital capacity were observed during the study, but measurements of FEV1 before and 2 h after drug administration indicated that celiprolol had no direct bronchodilating effect. The responsiveness to inhaled salbutamol was unaltered during the 12-month trial period, demonstrating that celiprolol does not block the beta 2-adrenoceptors on bronchial smooth muscle. Our results indicate that celiprolol is a safe long-term treatment for hypertension in asthmatic patients. Nevertheless, a survey of a large number of patients may be useful in order to detect individuals at risk, since sensitivity to beta-blockade may vary between patients.

A comparison of celiprolol and chlorthalidone in hypertensive patients with reversible bronchial obstruction.

The objective of this study was to evaluate the effects of celiprolol, a new beta-blocking drug, on the clinical condition and pulmonary function of hypertensive patients with reversible bronchial obstruction. Celiprolol was compared with chlorthalidone, an antihypertensive drug without known effect on bronchial tone. The study consisted of a 4-week placebo run-in period and a 12-week titration period in which the dose of both drugs was increased at 4-week intervals if blood pressure was not reduced adequately. The doses of celiprolol were 200, 400, or 600 mg once daily; those for chlorthalidone 12.5, 25, or 37.5 mg once daily. Entry criteria were a diastolic blood pressure between 90 and 115 mg Hg, and FEV-1 between 40% and 80% of predicted value, increasing by 15% or more after salbutamol, and a need for occasional bronchodilator therapy. Prophylactic medication for asthma was given in constant dosage for a month before the study and throughout the study. Preliminary results on 66 patients demonstrate that neither drug had a clinically significant effect on FEV-1, FEF 25-75, or FVC. Clinical variables were not significantly changed by either drug: the average monthly asthma attacks fell from 18 to 13 with celiprolol and from 11 to 7 with chlorthalidone. FEF was reduced by more than 50% in two patients on celiprolol and three on chlorthalidone. Monthly asthma attacks increased by more than 100% in five patients on celiprolol and four on chlorthalidone. Thus, preliminary results are unable to demonstrate adverse effects from celiprolol in patients with asthma and hypertension.

[Consequences of adult brachial plexus paralysis and its surgical treatment on respiratory function]. / Conséquences sur la fonction respiratoire des paralysies du plexus brachial de l'adulte et de leur traitement chirurgical.

The authors have studied 22 patients suffering from traumatic brachial plexus injuries and the consequences on respiratory function of paralysis of the diaphragm and other respiratory muscles. They have also studied the effects of some surgical treatment on respiratory function. The patients were divided into three groups: post-traumatic paralysis of the diaphragm (5 cases), patients who had had an intercostal neurotization (11 cases) and patients with paralysis of some respiratory muscles with an intact diaphragm (2 cases). Six tests were performed--vital capacity, total pulmonary capacity, residual functional capacity, airway resistance, maximum expiratory volume per second and airflow at 50 p. 100 of the vital capacity. Respiratory function was decreased by about 50 p. 100 in cases of diaphragmatic paralysis. This finding should be taken into consideration in cases of extensive lesions of the brachial plexus. The effects of intercostal neurotization were minimal when performed in cases with respiratory paralysis, but with an intact diaphragm. They were negligible in the absence of any respiratory paralysis. It is concluded that intercostal neurotization should not be performed in cases with diaphragmatic paralysis. In such cases, other types of neurotization are preferred.

[Effect of prolonged beta-adrenergic treatment on the ventilatory response to sympathomimetics]. / Effet d'un traitement bêta-adrénergique prolongé sur la résponse ventilatoire aux sympathomimétiques.

Ventilatory adrenergic responsiveness induced by long-term beta-mimetic treatment over three years were analysed in a study carried out in two groups of asthmatics. In group I, 11 patients received theophylline and oral beta-2-agonists; in group II, 7 patients received the same drugs and corticosteroids. Pulmonary function tests were serially performed with a body plethysmograph (Jaeger). The effect of beta adrenergic stimulation with 400 micrograms fenoterol was measured using variations of flow-volume curves. The mean increase of FEV1 after fenoterol was: in group I, 0.680 +/- 0.200 1 before treatment and 0.500 +/- 0.340 1 after beta adrenergic therapy; in group II, it was 0.550 +/- 0.340 1 before treatment and 0.510 +/- 0.350 1 after treatment (difference not statistically significant). For each patient, FEV1 variations were expressed in percent of optimum improvement. In most cases, there was a significant correlation between the two parameters (0.38 less than r less than 0.59), but the slopes of the regression curves differed from one patient to another. Intra-individual variation coefficient of the improvement of FEV1 has been calculated and showed large variations of the adrenergic pulmonary responses: from 34% to 98% of the mean improvement. Four patients only exhibited a significant and definitive decrease of their adrenergic response, which could be due to tachyphylaxis. But a transient loss of responsiveness to adrenergic stimulation has been found in all patients. Those cases were related to viral infections or allergen inhalations.

[Metabolism of beta-adrenergic substances. Therapeutic implications]. / Métabolisme des substances bêta-adreénergiques. Implications thérapeutiques.

The metabolism of the main beta-adrenoceptor stimulants which are not catechol derivatives involves conjugation with glucuronic or sulphuric acids in several animal species and conjugation with sulphuric acid in man. These drugs are not metabolized by MAO like isoproterenol or by COMT like the catechol derivatives: isoproterenol, trimetoquinol, hexoprenaline and rimiterol. Sulphate conjugation, in man, increases with the number of hydroxy groups. For salbutamol, pirbuterol, terbutaline and fenoterol, about 30%, 30%, 15% and 10% are respectively present in plasma as the unchanged active compound. Clenbuterol, a new specific beta 2-adrenoceptor stimulant, is a 4-amino-3,5 dichloro-benzene derivative and cannot be conjugated. It is cleared from the body mainly by the renal route (43% of the administered dose) and has eight minor metabolites, identical in several animal species and in man. Tulobuterol with no hydroxy substitute does not undergo conjugation, but is metabolized to 4-hydroxy tulobuterol. This metabolite is shown to be eight times more potent than tulobuterol. Metabolism depends greatly upon the route of administration: intravenous, subcutaneous, oral, by aerosol or instillation into the bronchial tree. Conjugation or COMT inactivation can take place in the gut wall (terbutaline), in lungs (isoproterenol, terbutaline, rimiterol) or by hepatic first-pass. These processes decrease the amount of drug reaching the blood and the receptor sites. Metabolism in the lung is important for ibuterol (terbutaline diisobutyrate), which is more lipophilic than terbutaline and spreads throughout tissues where it is hydrolyzed to active terbutaline. Biotransformations are determined by environmental or genetic factors and by the associated therapy and can change dramatically from one patient to another (interindividual variability) or for the same patient by multiple dosing (intra-individual variability). These differences in the rates of the metabolism can explain, partly, the differences observed in the response to beta-adrenoceptor stimulants by responder or non-responder patients. Decision about a therapeutic dosage regiment involves the choice of the drug, of the route of administration and of the dose. This choice is made on the basis of the dose/response relationship. In the kinetic approach, pharmacokinetic data obtained after a single dose facilitate the development of an appropriate dosage regimen.

Occupational allergy to sunflower pollen.

Although the sunflower belongs to the Compositeae family, allergy to sunflower pollen is not common. The occurrence of occupational allergy to this pollen species made it possible to characterize cross-reactive patterns of Compositeae pollens in a human experimental model. A 24-yr-old man developed rhinitis and conjunctivitis over 5 yr of exposure to sunflower pollens, and asthma developed during the fifth year. All respiratory and occular symptoms disappeared after he was removed from exposure, but he had a food allergic reaction while he was eating honey containing 30% sunflower pollens. The diagnosis of occupational allergy was based on history, skin prick tests and RAST to the pollen. Bronchial provocation tests performed after removal from exposure confirmed the sensitivity to sunflower pollens but there was no nonspecific hyperreactivity. It was found by RAST inhibition that sunflower pollen does not cross-react with other Compositeae pollens tested or with sunflower seed. The honey that elicited food intolerance was demonstrated to inhibit significantly sunflower pollen RAST.

[Effect of SCH 1000 on bronchial hyperreactivity compared to that of fenoterol]. / Effet du SCH 1000 sur l'hyperréactivité bronchique comparé à celui du fénotérol.

The hyperreactivity-modulating effect of SCH 1000 and fenoterol was tested in two groups of 10 patients. The drugs were administered at random, in simple blind fashion. Baseline pulmonary function was in the range of predicted values for all patients. One group received 80 micrograms of SCH 1000. When the drug was inhaled after carbachol challenge, pulmonary function returned to normal values in all patients. When the drug was inhaled before challenge, a shift to the right of the dose-effect curves was observed in all patients but 1. The other group received 800 micrograms of fenoterol. When the drug was administered after carbachol challenge, all 10 patients returned to baseline within 10 min. When it was given before carbachol challenge, a shift to the right of the dose-effect curves was observed in 9 patients out of 10. SCH 1000 and fenoterol induced an effective protection against carbachol, increasing the PD20 and shifting the dose-effect curves to the right in most of the asthmatics. In 2 patients, 80 micrograms of SCH 1000 or 800 micrograms of fenoterol seemed too low in order to achieve a complete protective effect.