ru-66647 and Asthma

Telithromycin is a ketolide, a semisynthetic derivative of the 14-membered ring macrolide antibiotics, with an expanded spectrum of activity relative to macrolides. Its good tissue pharmacokinetic characteristics allows once-daily administration, and it has been successfully employed in lower respiratory tract infections. Recent data indicate that telithromycin may exert anti-inflammatory/immunomodulatory effects that may be of use in the treatment of both acute and chronic airway diseases. This review examines the role of telithromycin in lower respiratory tract infections, analyzing published data on exacerbations of chronic bronchitis, community-acquired pneumonia and asthma in adults. In addition, pharmacokinetic and pharmacodynamic properties of the drug are considered.

Topics: Adult; Anti-Bacterial Agents; Asthma; Bronchitis, Chronic; Community-Acquired Infections; Humans; Ketolides; Pneumonia

We conducted a double-blind, randomized, placebo-controlled study to evaluate the efficacy of telithromycin in patients with acute exacerbations of asthma.. A total of 278 adults with diagnosed asthma were enrolled within 24 hours after an acute exacerbation of asthma requiring short-term medical care. The patients were randomly assigned to receive 10 days of oral treatment with telithromycin (at a dose of 800 mg daily) or placebo in addition to usual care. Primary efficacy end points were a change from baseline over the treatment period in symptoms (as recorded by patients in a diary card) and in the peak expiratory flow in the morning at home. The presence of Chlamydophila pneumoniae or Mycoplasma pneumoniae was ascertained by serologic analysis, polymerase chain reaction, and culture.. Of the two prespecified primary outcomes, only asthma symptoms showed a significantly greater reduction among patients receiving telithromycin than among those receiving placebo. Mean (+/-SD) scores on a test of asthma symptoms (on a 7-point scale, with 0 denoting no symptoms and 6 denoting severe symptoms) were 3.0+/-1.4 at baseline and 1.7+/-1.1 at the end of treatment for the telithromycin group and 2.8+/-1.3 at baseline and 2.0+/-1.0 at the end of treatment for the placebo group. The mean decrease in symptom scores during the treatment period was 1.3 for telithromycin and 1.0 for placebo (mean difference, -0.3; 95 percent confidence interval, -0.5 to -0.1; P=0.004). There was no significant treatment effect on the other primary outcome measure, a change in morning peak expiratory flow. Nausea was more common among patients in the telithromycin group than in the placebo group (P=0.01). Although 61 percent of patients had evidence of infection with C. pneumoniae, M. pneumoniae, or both, there was no relationship between bacteriologic status and the response to asthma treatment.. This study provides evidence of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear. (ClinicalTrials.gov number, NCT00273520.).

Topics: Acute Disease; Administration, Oral; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Anti-Bacterial Agents; Asthma; Chlamydophila Infections; Chlamydophila pneumoniae; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Ketolides; Male; Middle Aged; Mycoplasma pneumoniae; Peak Expiratory Flow Rate; Pneumonia, Mycoplasma; Treatment Outcome

Topics: Anti-Bacterial Agents; Asthma; Forced Expiratory Volume; Humans; Ketolides

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Albuterol; Anti-Bacterial Agents; Asthma; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Ketolides; Salmeterol Xinafoate

Topics: Acute Disease; Adrenal Cortex Hormones; Anti-Bacterial Agents; Asthma; Forced Expiratory Volume; Health Services Misuse; Humans; Ketolides

Topics: Acute Disease; Anti-Bacterial Agents; Asthma; Gastroesophageal Reflux; Humans; Ketolides

Topics: Anti-Bacterial Agents; Asthma; Drug Interactions; Drug Resistance, Bacterial; Humans; Ketolides; Macrolides; Theophylline

Topics: Anti-Bacterial Agents; Asthma; Bacterial Infections; Drug Approval; Humans; Ketolides; Liver Failure, Acute; Product Surveillance, Postmarketing; United States; United States Food and Drug Administration

The potential of the novel ketolide antimicrobial agents, HMR 3004 and HMR 3647, to antagonize the injurious effects of the bioactive phospholipids (PL), platelet-activating factor (PAF), lyso-PAF, and lysophosphatidylcholine (LPC) on the ciliary beat frequency and structural integrity of human ciliated respiratory epithelium in vitro was investigated, in the presence or absence of polymorphonuclear leukocytes (PMNL). The ciliary beat frequency of human nasal respiratory epithelium, obtained by nasal brushing of healthy volunteers, was measured using a photo-transistor technique, while superoxide generation by activated human PMNL and membrane-stabilizing activity were measured by lucigenin-enhanced chemiluminescence and haemolytic procedures, respectively. All three PL, at concentrations of 2.5 microg x mL(-1), caused significant (p<0.005) ciliary slowing and epithelial damage, while treatment of the epithelial strips with the ketolides, in particular HMR 3004, caused dose-related attenuation of these direct adverse effects of the PL on ciliated epithelium, apparently by a membrane-stabilizing mechanism. When epithelial strips were exposed to the combination of PMNL (1 x 10(6) cells x mL(-1)) and PAF (1 microg x mL(-1)), significant ciliary dysfunction and epithelial damage were also observed, which were mediated predominantly by neutrophil-derived oxidants. These injurious effects of PAF were antagonized by preincubation of the epithelial strips or the PMNL with HMR 3004 (10 microg x mL(-1)). The ketolide antimicrobial agents, in particular HMR 3004, antagonize the direct and polymorphonuclear leukocyte-mediated injurious effects of phospholipids on human ciliated epithelium and may have beneficial effects in inflammatory disorders of the airways, such as asthma, chronic bronchitis, diffuse panbronchiolitis and bronchiectasis.

Topics: Anti-Bacterial Agents; Asthma; Catalase; Epithelium; Humans; Ketolides; Macrolides; Mucociliary Clearance; Nasal Mucosa; Neutrophils; Phospholipids; Superoxide Dismutase