oxadiazoles and Tuberculosis--Pulmonary

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

Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, "green" β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.

Topics: Administration, Inhalation; Animals; Antitubercular Agents; beta-Cyclodextrins; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Synergism; Drug Therapy, Combination; Ethionamide; Female; Humans; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nanoparticles; Oxadiazoles; Piperidines; Polylactic Acid-Polyglycolic Acid Copolymer; RAW 264.7 Cells; Solubility; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis (TB) is one of the deadliest infectious diseases and comprises a global public health concern because co-infection with Human immunodeficiency virus (HIV) and, in particular, the continuous isolation of new Multidrug-resistant strains (MDR), rendering the discovery of novel anti-TB agents a strategic priority. One of the most effective first-line mycobactericidal drugs is Isoniazid (INH). Previously, we reported in vitro anti-mycobacterial activity against sensitive and MDR Mycobacterium tuberculosis strains of a new oxadiazole obtained from the hybridization of INH and palmitic acid. The present study evaluated the therapeutic potential of liposomes including Phosphatidylcholine (PC) and L-α Phosphatidic acid (PA) or PC and Cholesterol (Chol) containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in BALB/c male mice infected by intratracheal (i.t.) route with drug-sensitive or MDR M. tuberculosis.. The lipophilic 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine was obtained to mix INH and palmitoyl chloride. The in vivo anti-TB effect of this oxadiazole derivative contained in two different liposomes was tested in BALB/c mice infected with a sensitive strain of M. tuberculosis, initiating treatment 2 months post-infection, by i.t. route, of 50 μg of oxadiazole derivative for 1 month. In a second stage, mice were infected with an MDR (resistant to first-line drugs) and treated with 150 μg of an oxadiazole derivative carried by PC + Chol liposomes for 2 months. The effect of the oxadiazole derivative in vivo was determined by the quantification of lung bacilli loads and histopathology.. In comparison with control animals, drug-sensitive, strain-infected mice treated for 1 month with 50 μg of this oxadiazole derivative contained in the liposomes of PC + Chol showed a significant, 80% decrease of live bacilli in lungs, which correlated with the morphometric observation, and the group of MDR clinical isolate-infected mice treated with 150 μg of the oxadiazole derivative contained in the same type of liposome showed significantly lower lung bacillary loads than control mice, producing 90% of bacilli burden reduction after 2 months of treatment.. These results confirm and extend the reported highly efficient anti-mycobacterial activity of this lipophilic oxidazole derivative when it is carried by liposomes in mice suffering from late progressive pulmonary TB induced by drug-sensitive, and most prominently by, MDR strains.

Topics: Animals; Antitubercular Agents; Cholesterol; Disease Models, Animal; Isoniazid; Liposomes; Male; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Oxadiazoles; Phosphatidic Acids; Phosphatidylcholines; Pyridines; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Anti-Inflammatory Agents; Antitussive Agents; Humans; Oxadiazoles; Respiratory System; Respiratory Tract Infections; Tuberculosis; Tuberculosis, Pulmonary

Topics: Antitussive Agents; Bronchitis; Humans; Oxadiazoles; Respiratory System; Respiratory Tract Diseases; Tetracycline; Tuberculosis; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Biomedical Research; Blood; Cycloserine; Drug Resistance; Drug Resistance, Microbial; Ethionamide; Isoniazid; Mice; Oxadiazoles; Pharmacology; Pneumothorax; Pneumothorax, Artificial; Pyrazinamide; Radiography, Thoracic; Sputum; Streptomycin; Toxicology; Tuberculosis; Tuberculosis, Pulmonary; Urine

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