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Biomedical subjects

P Godard

Publications and source records attributed to P Godard.

At least 19 recordsLinked to original sources
PubMed2000

[Allergy to macrolides. 21 cases].

OBJECTIVE: Allergic drug reactions to macrolides are extremely rare and there is little information in the literature concerning relevant diagnostic tests. PATIENTS AND METHODS: Twenty-one patients were recently seen for assumed allergies (principally urticaria) to diverse macrolides. Skin tests (prick and intradermal tests) were performed with injectable forms of spiramycin and erythromycin. Seventeen out of 21 patients were provoked under strict hospital surveillance. RESULTS: Only 3 patients had a positive provocation test and were thus truly allergic (to spiromycin). They had positive skin tests to both macrolides tested. CONCLUSION: Most hypersensitivity reactions to macrolides are therefore diagnosed with provocation tests.

Adolescent↗
PubMed2000

[Allergy to macrolide antibiotics. Review of the literature].

MACROLIDE CLASSES: Macrolides are characterized by their basic structure made up of a lactonic cycle with 2 osidic chains. They are classified according to the number of carbon atoms in the cycle: 14-membered macrolides (erythromycin, troleandomycin, roxithromycin, dirithromycin, clarithromycin), 15-membered macrolides (azithromycin) and 16-membered macrolides (spiramycin, josamycin, midecamycin). MACROLIDE ALLERGY: Allergy to macrolides is extremely rare (0.4% to 3% of treatments). The little information available in the literature is insufficient to establish the usefulness of diagnostic tests. An immediate IgE-dependent hypersensitivity has been shown with erythromycin in some cases but the mechanism remains unknown and skin tests are quite often negative. Clinical manifestations are the same as those encountered with beta-lactams. It would appear that macrolide allergies are unlikely to be class allergies. This is important as eviction advice could be limited to the single causal macrolide.

Anti-Bacterial Agents↗
PubMed2000

Structural consequences of airway inflammation in asthma.

Asthma represents a chronic inflammatory process of the airways followed by healing, the end-result of which is an altered structure referred to as a remodeling of the airways. Repair usually involves 2 distinct processes: regeneration (which is the replacement of injured tissue by parenchymal cells of the same type) and replacement by connective tissue and its eventual maturation into scar tissue. In many instances both processes contribute to the healing response and inflammation. In asthma the processes of cell dedifferentiation, migration, differentiation, and maturation and connective tissue deposition can be followed either by complete or altered restitution of airway structure and function, the latter often seen as fibrosis and increase in smooth muscle and mucus gland mass. These features result in an increased resistance to airflow, particularly when there is bronchial contraction and bronchial hyperresponsiveness. The effect on airflow is compounded by the presence of increased mucous secretion and inflammatory exudate, which not only blocks the airway passages but also causes an increased surface tension that favors airway closure.

Animals↗
PubMed2000

Transcriptional potencies of inhaled glucocorticoids.

Glucocorticoids (GC) are the most effective anti-inflammatory drugs used in asthma. By a process called trans-activation, they increase the transcription of genes involved in either beneficial processes or certain side effects. Through trans-repression, they inhibit the transcription factors nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1), thereby decreasing the expression of many genes encoding inflammatory mediators such as the cytokine RANTES. We have measured the trans-activation and trans-repression potencies of the five currently available inhaled GC using reporter gene assays. The rank order of trans-activation potencies in HeLa cells stably transfected with a GC-inducible luciferase gene was fluticasone propionate > budesonide and triamcinolone acetonide > beclomethasone dipropionate and flunisolide. For all GC except beclomethasone dipropionate, there was a highly significant correlation between their potency to trans-activate in HeLa cells and their capacity to induce the gluconeogenic enzyme tyrosine aminotransferase in hepatoma tissue culture (HTC) cells. The rank order of trans-repression potencies in A549 lung cells transiently transfected with an AP-1- or NF-kappaB-dependent luciferase gene was fluticasone propionate > budesonide > beclomethasone dipropionate, triamcinolone acetonide, and flunisolide. The same rank order was found for inhibition of RANTES release. Thus, determination of trans-repression and trans-activation potencies of GC may help to predict their capacity to produce anti-inflammatory and side effects, respectively.

Administration, Inhalation↗
PubMed2000

Glucocorticoid receptor alpha and beta in glucocorticoid dependent asthma.

Patients with glucocorticoid (GC)-dependent asthma present an ongoing inflammation of the airways despite chronic long-term treatment with oral GC. Interleukin (IL)-8 and granulocyte/macrophage colony-stimulating factor (GM-CSF) have been implicated in airway inflammation in severe asthma and their synthesis is normally repressed by GC. To further characterize the inflammatory process in GC-dependent asthma, we measured the release of IL-8 and GM-CSF by peripheral blood mononuclear cells (PBMC) of eight normal subjects, six untreated controlled asthmatics, six untreated uncontrolled asthmatics, and nine GC-dependent asthmatics. We show that PBMC from GC-dependent asthmatics released high amounts of these cytokines despite chronic in vivo exposure to GC (p < 0.001 versus normal subjects). In contrast, when untreated uncontrolled asthmatics were given a short course of oral GC, IL-8 and GM-CSF production was inhibited (p = 0.0078). Release of IL-8 and GM-CSF by PBMC of GC-dependent asthmatics was reduced after in vitro GC treatment (p < 0.002). We investigated whether the incapacity of GC to inhibit production of these cytokines in vivo was the result of a dysregulation of the glucocorticoid receptor (GR) in GC-dependent asthma. GRalpha and GRbeta are, respectively, the functional receptor and a putative dominant negative form of the receptor. Western blot and polymerase chain reaction (PCR) analyses indicated that GRalpha was expressed at similar level in all groups and was largely predominant over GRbeta. Thus, persistent release of IL-8 and GM-CSF in GC-dependent asthma is not associated with low expression of GRalpha or overexpression of GRbeta.

Adult↗
PubMed1999

Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients.

OBJECTIVE: To determine the ability of montelukast, a leukotriene receptor antagonist, to allow tapering of inhaled corticosteroids in clinically stable asthmatic patients. DESIGN: Double blind, randomised, placebo controlled, parallel group study. After a single blind placebo run in period, during which (at most) two inhaled corticosteroids dose decreases occurred, qualifying, clinically stable patients were allocated randomly to receive montelukast (10 mg tablet) or matching placebo once daily at bedtime for up to 12 weeks. SETTING: 23 academic asthma centres in United States, Canada, and Europe. PARTICIPANTS: 226 clinically stable patients with chronic asthma receiving high doses of inhaled corticosteroids (113 randomised to montelukast and 113 to placebo). INTERVENTIONS: Every 2 weeks, the inhaled corticosteroids dose was tapered, maintained, or increased (rescue) based on a standardised clinical score. MAIN OUTCOME MEASURES: Last tolerated dose of inhaled corticosteroids. RESULTS: Compared with placebo, montelukast allowed significant (P=0. 046) reduction in the inhaled corticosteroid dose (montelukast 47% v placebo 30%; least square mean difference 17.6%, 95% confidence interval 0.3 to 34.8). Fewer patients on montelukast (18 (16%) v 34 (30%) placebo, P=0.01) required discontinuation because of failed rescue. CONCLUSIONS: Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control.

Acetates↗
PubMed1999

[Corticosteroid-resistant asthma: basic aspects].

A CONTROVERSIAL DEFINITION: The current definition of corticosteroid-resistant asthma is a spirometry definition. There is however, no consensus on dose, treatment duration, steroid administration route and the degree of FEV1 non-reversibility allowing the diagnosis of corticosteroid-resistant asthma. Finally, the beneficial effect of steroids in clinical terms (symptom frequency, number of hospitalizations, quality of life) is not taken into consideration, thus nearly one-half al all patients included in studies on corticosteroid resistance are taking long-term oral steroids. This subgroup of patients must be considered individually when examining these studies. COMPLEX PATHOGENESIS: There are a wide range of anomalies described in the literature involving: glucocorticoid pharmacokinetics, cytokine regulation, cell function (monocytes, lymphocytes, eosionophils), and transcription factors (glucocorticoid and AP-1 receptors). DIFFICULT THERAPEUTIC MANAGEMENT: There are several prerequisites before proposing exceptional regimens using cyclosporine, gold salts, methotrexate, or immunoglobulins: i) certain diagnosis of asthma (with CT scan and ultrasonographic explorations if needed, ii) proper control of environmental factors and good compliance, iii) proof of the absence of clinical benefit with long-term corticosteroids. These exceptional therapeutic schemes have their disadvantages and are only warranted by clinically patent corticosteroid resistance (whatever the "biological" cause).

Adrenal Cortex Hormones↗
PubMed1999

Eosinophilic inflammation assessed by induced sputum in corticosteroid-dependent asthma.

Sputum induction can be used to study airway inflammation in asthmatics. However, it has not been used in patients with corticosteroid-dependent asthma requiring long-term oral corticosteroids. The aim of the study was to assess the number of eosinophils and the levels of eosinophil cationic protein (ECP) in sputum of 17 corticosteroid-dependent asthmatics by comparison with nine mild untreated asthmatics, 10 moderate asthmatics receiving inhaled steroids (ICS) and 11 healthy subjects. In the 17 corticosteroid-dependent asthmatics, we examined sputum eosinophil markers on two occasions and correlated with the control of asthma. Eosinophils were undetectable in controls and were detected in 63.8% of asthmatics. There were no significant differences between the three groups of asthmatics. ECP levels were significantly increased in ICS or corticosteroid-dependent asthmatics by comparison to controls and mild asthmatics. There was no significant difference between ICS and corticosteroid-dependent asthmatics. During follow-up, corticosteroid-dependent asthmatics with a controlled disease had no significant change in eosinophil numbers or ECP levels. On the other hand, corticosteroid-dependent asthmatics with recent exacerbations had a non-significant increase in eosinophil numbers and a significant increase in ECP levels. This study shows that ECP levels may be more accurate than eosinophil numbers in assessing exacerbations in corticosteroid-dependent asthmatics.

Adolescent↗
PubMed1999

A comparison of two long-acting beta-agonists, oral bambuterol and inhaled salmeterol, in the treatment of moderate to severe asthmatic patients with nocturnal symptoms. The French Bambuterol Study Group.

This multicentre study was set up to compare the efficacies of two long-acting beta 2-agonists, oral bambuterol (20 mg nocte) and inhaled salmeterol (50 micrograms b.i.d.), for the treatment of moderate to severe asthmatics who were considered to be on optimal steroid/bronchodilator therapy, but continued to have troublesome nocturnal symptoms. The study was of double-blind, parallel-group design and comprised a 2-week run-in on previous maintenance therapy followed by a 6-week study treatment period. There were 117 randomized asthmatic patients aged 20-70 years (65 women and 52 men with a mean age of 45 and predicted FEV1 of 64%), who had been taking 800-2000 micrograms inhaled steroid and/or up to 20 mg oral steroid per day for at least 4 weeks. They were asked to complete daily diary cards, recording morning and evening PEF, daily symptoms, nocturnal awakenings, rescue medication and subjective tremor. There was a significant increase in both morning and evening PEF respectively, on bambuterol (28 l min-1, 20 l min-1, P < 0.05) and salmeterol (29 l min-1, P < 0.001; 23 l min-1, P < 0.01) when compared with run-in. The mean percentage fall in overnight PEF was reduced by 8.3% (P < 0.001) on bambuterol and by 6.8% (P < 0.001) on salmeterol. Nocturnal awakenings and daytime symptoms due to asthma were significantly lowered by both treatments, as was the consumption of rescue bronchodilator. Tremor scores were very low during both run-in and study treatments. No significant treatment difference between bambuterol and salmeterol was detected for any of the above variables. Once-daily oral bambuterol provides a highly effective alternative to twice-daily inhaled salmeterol for relief of nocturnal symptoms in patients with moderate to severe asthma.

Administration, Inhalation↗
PubMed1999

Safety and cellular assessment of bronchial brushing in airway diseases.

Bronchial brushing is a useful method for morphological and functional studies of bronchial epithelial cells (BECs) in various diseases. This technique has been found to be generally safe, but its safety in asthma and chronic bronchitis has not been fully assessed. The purpose of this study was to determine 1, whether bronchial brushing is a safe method in asthmatic and chronic bronchitis patients of differing severity and 2, to characterize the BECs obtained in terms of number, viability and purity. We evaluated 25 asthmatics of variable severity, 19 chronic bronchitis patients and 26 normal volunteers. Bronchoscopy and bronchial brushing were performed in a standardized manner by the same investigator. Safety was assessed by clinical follow-up of all subjects; continuous monitoring of arterial oxygen saturation during the procedure with a digital oximeter was carried out in a subsample of subjects. No complications were observed clinically during the procedure. There was a minimal fall in arterial oxygen saturation without a significant difference between the three groups of subjects. A consistent number of BECs was recovered and their viability, assessed by the trypan blue exclusion test, in asthmatics and chronic bronchitis patients was significantly lower than in controls (P < 0.05). Bronchial brushing is well tolerated and may be a valuable method of obtaining BECs in asthmatic and chronic bronchitis patients.

Adult↗
PubMed1999

Predictive capacity of histamine release for the diagnosis of drug allergy.

BACKGROUND: The diagnosis of immediate allergic reactions to drugs is difficult, requiring in vitro test development. Basophils are likely to be involved in these reactions, and to evaluate the sensitivity, the specificity, and the predictive values of the histamine-release test, we performed a prospective study in 68 patients tested for suspected drug allergy. METHODS: Positive diagnosis was established by history, skin tests, and, if needed, oral provocation tests. Histamine release in the presence of the drug was assessed on heparinized whole blood by enzyme immunoassay (Immunotech, France), and the cutoff value was set at 5% of total histamine content. Spontaneous and anti-IgE-induced histamine release was also studied in all subjects. RESULTS: All patients presented to our clinic with reactions ranging from maculopapular exanthema to anaphylactic shock. Thirty-five patients had proven drug allergy; 33 were not allergic to drugs and served as a control group together with 40 other subjects with no history of drug allergy. Net histamine release was positive in 18/35 allergics and 27/73 nonallergics, giving poor sensitivity (51.4%), specificity (63.0%), and positive predictive value (29.3%), but valuable negative predictive value (81.1%). CONCLUSIONS: The usefulness of the in vitro histamine-release test for the diagnosis of drug allergy appears to be insufficient.

Acetaminophen↗
PubMed1999

The glucocorticoid receptor gene as a candidate for gene therapy in asthma.

Glucocorticoids (GC) are commonly used as anti-inflammatory drugs in asthma, but can produce serious secondary effects and, moreover, be inefficient in corticoresistant asthmatics. After binding to the glucocorticoid receptor (GR), they repress the synthesis of proinflammatory cytokines via inhibition of the transcription factors AP-1 and NF-kappa B. Since qualitative and quantitative defects of the GR have been reported in corticoresistant patients, the transfer of the GR gene in the lung epithelium, the primary site of inflammation in asthma, may restore sensitivity to GC in these patients. As a prerequisite to in vivo studies, we have transfected A549 human lung epithelial cells with a GR expression vector. Using AP-1 and NF-kappa B-dependent reporter gene assays and an immunoassay for the pro-inflammatory cytokine RANTES, we show that the over-expressed GR significantly repressed AP-1 and NF-kappa B activities in the absence of hormone and that the GC dexamethasone produced an additive inhibitory effect. The GC-independent repression of AP-1 and NF-kappa B activities was further demonstrated by overexpressing a ligand-binding deficient GR mutant. Our data suggest that delivery of the GR gene in vivo may reduce inflammation without recourse to GC and may constitute an alternative therapeutic approach for corticoresistant asthma.

Animals↗
PubMed1999

VEGF levels in asthmatic airways do not correlate with plasma extravasation.

BACKGROUND: Vascular permeability/vascular endothelial growth factor (VEGF) is a multifunctional cytokine which plays a role in chronic inflammation and angiogenesis. Its expression in bronchoalveolar lavage (BAL) has not been determined although VEGF may be relevant to the pathophysiology of asthma in which oedema is an important feature. METHODS: We studied VEGF, albumin and IgA immunoreactive levels in the BAL fluids obtained from 27 chronic stable asthmatics, nine untreated chronic bronchitis patients and 15 control subjects. RESULTS: BAL fluid levels of VEGF and VEGF normalized to IgA were not significantly different in any patient group. Both asthmatic steroid- and non-steroid-treated groups had significantly lower albumin levels in their BAL fluids explaining most of the 179% increased VEGF normalized to albumin ratios in non-steroid treated asthmatics. Moreover, VEGF and albumin markers correlated in control subjects (r = 0.73, P = 0.006) and in chronic bronchitics (r = 0.75, P = 0.03, Spearman test), but not in asthmatics. VEGF was inversely correlated with asthma severity (GINA/NHLBI scores) in non-steroid treated asthmatics (tau = - 0.52, P = 0.009, Kendall test). CONCLUSIONS: Thus, the potential role of VEGF in asthma requires further studies on bronchial biopsies and induced sputum.

Adult↗
PubMed1999

Comparison between nasal and bronchial inflammation in asthmatic and control subjects.

Although asthma and rhinitis often coexist, it is still unknown whether they are characterized by a similar inflammatory profile. We studied eosinophilic infiltration, epithelial shedding and reticular basement membrane thickness in nasal and bronchial biopsies of six control subjects, 15 untreated allergic asthmatics with perennial rhinitis, and six corticosteroid-dependent (CSD) asthmatics. In nasal and bronchial biopsies, eosinophils were greater in untreated asthmatics than in control subjects and CSD asthmatics (p = 0.001). In untreated asthmatics, eosinophils were higher in bronchial than in nasal biopsies (p = 0.002). In nasal and bronchial biopsies, reticular basement membrane thickness was greater in untreated and CSD asthmatics than in control subjects (nasal: p < 0.008 and p < 0. 004; bronchial: p < 0.001 and p < 0.008). In untreated and CSD asthmatics, reticular basement membrane thickness was greater in bronchial than in nasal biopsies (p = 0.001; Wilcoxon's W test). Nasal epithelium was not shed in all the study groups. In untreated asthmatics, bronchial epithelium shedding was greater than in control subjects or CSD asthmatics (p < 0.005), and it was greater than nasal epithelium shedding (p < 0.006). This study has shown that, although concomitant, the extent of eosinophilic inflammation of reticular basement membrane thickness and of the epithelium shedding is greater in bronchial than in nasal mucosa of asthmatic patients with perennial rhinitis.

Adolescent↗