title: Inhalable microparticles containing isoniazid and rifabutin target macrophages and 'stimulate the phagocyte' to achieve high efficacy.
abstract: Macrophage responses to infection with Mycobacterium tuberculosis (MTB) and treatment with soluble isoniazid (INH) plus rifabutin (RFB) versus microparticles containing equivalent amounts of drugs were compared. It was investigated whether macrophages driven to alternative activation upon infection with MTB could be rescued to display the classical activation phenotype. It was established that microparticles sustain high levels of drugs in cytosol of macrophages for longer period as compared to soluble drugs. Microparticles co-localized with intracellular bacteria, and induced a variety of innate bactericidal responses, including induction of free radicals, alteration of mitochondrial membrane potential and apoptosis. The data strongly suggest that additional benefit may be derived from the nature of the drug delivery system, which fulfils Koch's dictum 'stimulate the phagocyte' for curing tuberculosis.
authors.affiliation: Pharmaceutics Division, Central Drug Research Institute, Lucknow 226 001, India.
authors.forename: Awadh Bihari
authors.initials: AB
authors.lastname: Yadav
authors.forename: Rolee
authors.initials: R
authors.lastname: Sharma
authors.forename: Pavan
authors.initials: P
authors.lastname: Muttil
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Rahul Kumar
authors.initials: RK
authors.lastname: Verma
authors.forename: Mradul
authors.initials: M
authors.lastname: Mohan
authors.forename: Sanjay Kumar
authors.initials: SK
authors.lastname: Patel
authors.forename: Amit
authors.initials: A
authors.lastname: Misra
mesh_terms: D000280:Administration, Inhalation; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology; D053938:DNA Fragmentation; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010316:Particle Size; D010586:Phagocytes / Q000187:drug effects* / Q000378:metabolism; D017828:Rifabutin / Q000008:administration & dosage / Q000494:pharmacology; D014376:Tuberculosis / Q000276:immunology
chemical_list: D000995:Antitubercular Agents; D017828:Rifabutin; D007538:Isoniazid