title: Inhalable Particles for "Pincer Therapeutics" Targeting Nitazoxanide as Bactericidal and Host-Directed Agent to Macrophages in a Mouse Model of Tuberculosis.
abstract: Nitazoxanide (NTZ) has moderate mycobactericidal activity and is also an inducer of autophagy in mammalian cells. High-payload (40-50% w/w) inhalable particles containing NTZ alone or in combination with antituberculosis (TB) agents isoniazid (INH) and rifabutin (RFB) were prepared with high incorporation efficiency of 92%. In vitro drug release was corrected for drug degradation during the course of study and revealed first-order controlled release. Particles were efficiently taken up in vitro by macrophages and maintained intracellular drug concentrations at one order of magnitude higher than NTZ in solution for 6 h. Dose-dependent killing of Mtb and restoration of lung and spleen architecture were observed in experimentally infected mice treated with inhalations containing NTZ. Adjunct NTZ with INH and RFB cleared culturable bacteria from the lung and spleen and markedly healed tissue architecture. NTZ can be used in combination with INH-RFB to kill the pathogen and heal the host.
authors.affiliation: CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: National Institute of Immunology , New Delhi 110067, India.
authors.forename: Jairam
authors.initials: J
authors.lastname: Meena
authors.affiliation: CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.affiliation: National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR) , Agra 282001, India.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Gupta
authors.affiliation: National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR) , Agra 282001, India.
authors.forename: Umesh Dutta
authors.initials: UD
authors.lastname: Gupta
authors.affiliation: CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Sadan
authors.initials: S
authors.lastname: Kumar
authors.affiliation: CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Sharad
authors.initials: S
authors.lastname: Sharma
authors.affiliation: National Institute of Immunology , New Delhi 110067, India.
authors.forename: Amulya K
authors.initials: AK
authors.lastname: Panda
authors.affiliation: CSIR-Central Drug Research Institute , Lucknow 226031, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Misra
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D009574:Nitro Compounds; D011880:Radiotherapy Planning, Computer-Assisted; D017828:Rifabutin / Q000008:administration & dosage / Q000627:therapeutic use; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D009574:Nitro Compounds; D013844:Thiazoles; D017828:Rifabutin; C041747:nitazoxanide; D007538:Isoniazid
keywords: autophagy; host-directed therapies; macrophage targeting; microparticles; pulmonary drug delivery; tuberculosis