oxadiazoles and Cough

In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA. We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg·kg(-1)) or higher dose (10, 10 and 20 mg·kg(-1)). The study enrolled 19 patients (10 males and nine females aged 19-57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p<0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p<0.001) and 56% (p = 0.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild. Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability.

Topics: Adult; Codon, Nonsense; Codon, Terminator; Cough; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Male; Middle Aged; Oxadiazoles; Prognosis; Ribosomes; Treatment Outcome

Topics: Aged; Antitussive Agents; Capsaicin; Cough; Cross-Over Studies; Female; Humans; Male; Middle Aged; Oxadiazoles; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Single-Blind Method

Topics: Adult; Aged; Antitussive Agents; Bromhexine; Bronchial Diseases; Bronchial Spasm; Carbocysteine; Clinical Trials as Topic; Cough; Cysteine; Drug Combinations; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines

Topics: Acute Disease; Adult; Aged; Antitussive Agents; Benzhydryl Compounds; Chronic Disease; Clinical Trials as Topic; Codeine; Cough; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines; Propanolamines

Topics: Adult; Aged; Antitussive Agents; Asthma; Bronchitis; Child; Clinical Trials as Topic; Cough; Evaluation Studies as Topic; Humans; Infant; Infant, Newborn; Neoplasms; Oxadiazoles; Pneumonia; Tuberculosis, Pulmonary

Topics: Adult; Antitussive Agents; Clinical Trials as Topic; Cough; Humans; Oxadiazoles

Topics: Antitussive Agents; Clinical Trials as Topic; Codeine; Cough; Humans; Oxadiazoles; Placebos

CH-13584 (formerly: KHL-8425, 1H-purine-2,6-dione, 3,7-dihydro-3-methyl-7[(5-methyl-1,2,4-oxadiazol-3-yl)methyl], CAS 115779-20-9) showed antitussive effect on the citric acid spray-induced cough model. The antitussive effect of p.o. CH-13584 was antagonised by i.m. or intracerebroventricular (i.c.v.) naloxone, i.m. nor-binaltorphimine or s.c. beta-funaltrexamine. Intracerebroventricular administration of CH-13584 induced long-lasting antitussive effect which was antagonised by coadministration of i.c.v. naloxone. CH-13584 did not bind to opioid mu, delta, kappa receptor in vitro or inhibit the [3H]diprenorphine binding in vivo. Two-week treatment with CH-13584 up to the dose of 100 mg/kg p.o. did not produce autonomic and behavioural signs of withdrawal induced either by drug withdrawal or by naloxone injection, while morphine and codeine induced characteristic opioid-type physical dependence in rats.

Topics: Animals; Antitussive Agents; Binding, Competitive; Cough; Guinea Pigs; Injections, Intraventricular; Male; Mice; Narcotic Antagonists; Oxadiazoles; Purines; Rats; Rats, Wistar; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders

CH-13584 (formerly: KHL-8425, 1H-purine-2,6-dione, 3,7-dihydro-3-methyl-7[(5-methyl-1,2,4-oxadiazol-3-yl)methyl], CAS 115779-20-9) is a new xanthine derivative synthesized with the purpose to develop a highly safe compound against several pulmonary disorders, especially for the treatment of acute and chronic cough. CH-13584 showed acute and chronic antitussive activity on citric acid spray-evoked cough model in guinea-pig. CH-13584 was also effective on capsaicine spray and mechanical irritation-induced cough in guinea-pig and rabbit, respectively. The effectivity of CH-13584 on antitussive tests reached and in some cases even exceeded the effectivity of the reference compounds. The compound increased the mucociliary clearance at lower doses than bromhexine.

Topics: Animals; Antitussive Agents; Capsaicin; Citric Acid; Cough; Female; Guinea Pigs; In Vitro Techniques; Male; Mucociliary Clearance; Oxadiazoles; Physical Stimulation; Purines; Rabbits

Topics: Animals; Antitussive Agents; Codeine; Cough; Guinea Pigs; Humans; Lethal Dose 50; Mice; Oxadiazoles; Piperidines; Rabbits; Rats

Topics: Animals; Antitussive Agents; Cough; Diphenhydramine; Drug Combinations; Humans; Mice; Oxadiazoles; Piperidines

Topics: Cough; Diphenhydramine; Drug Synergism; Humans; Oxadiazoles

Topics: Animals; Antitussive Agents; Cats; Codeine; Cough; Guinea Pigs; In Vitro Techniques; Mice; Oxadiazoles; Papaverine; Rats

Topics: Adolescent; Anti-Inflammatory Agents; Antitussive Agents; Asthma; Child; Common Cold; Cough; Oxadiazoles; Rhinitis, Allergic, Seasonal; Toxicology

Topics: Analgesics; Analgesics, Non-Narcotic; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antipyretics; Antitussive Agents; Asthma; Bronchitis; Bronchopneumonia; Cough; Humans; Oxadiazoles

Topics: Bronchitis; Cough; Disease; Humans; Inflammation; Oxadiazoles; Trachea

Topics: Cough; Oxadiazoles

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Bronchitis; Bronchopneumonia; Child; Cough; Infant; Measles; Oxadiazoles

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Cough; Hospitals; Oxadiazoles

Topics: Anti-Inflammatory Agents; Cough; Humans; Inflammation; Oxadiazoles

Topics: Cough; Inflammation; Oxadiazoles

Topics: Carbonic Anhydrases; Cough; Humans; Oxadiazoles; Prothrombin; Prothrombin Time; Tuberculosis; Tuberculosis, Pulmonary

Topics: Bronchitis; Cough; Humans; Oxadiazoles; Recurrence

Topics: Cough; Humans; Oxadiazoles

Topics: Cough; Humans; Oxadiazoles

Topics: Asthma; Cough; Humans; Oxadiazoles; Syndrome

Topics: Bronchitis; Bronchitis, Chronic; Cough; Humans; Oxadiazoles

Topics: Antitussive Agents; Cough; Humans; Oxadiazoles

Topics: Cough; Humans; Oxadiazoles

Topics: Cough; Humans; Oxadiazoles

Topics: Aged; Aged, 80 and over; Aging; Bronchitis; Cough; Humans; Oxadiazoles

Topics: Bronchitis; Child; Cough; Humans; Infant; Oxadiazoles; Pediatrics