title: Efficacy of clofazimine-modified cyclodextrin against Mycobacterium avium complex in human macrophages.
abstract: Clofazimine, a water insoluble substituted iminophenazine derivative with anti-mycobacterial and anti-inflammatory activity, is recommended by the WHO for the treatment of leprosy. It is also active against disseminated Mycobacterium avium complex (MAC) disease in HIV-infected patients. Recently, we achieved a 4000-fold increase of clofazimine water solubility using a novel modified clofazimine-cyclodextrin complex synthesized and patented by our group [Wasserlösliche, Iminiophenazinderivate enthaltende pharmazeutische Zusammensetzungen, deren Herstellung und Verwendung, German Patent, DE19814814C2]. In this paper we examine the activity of this complex against MAC in human macrophages, and evaluate its cytotoxicity. MAC-infected macrophages were treated for 24h with free or complexed clofazimine. The in vitro minimum inhibitory concentrations of both free and complexed clofazimine were 0.1 microg/ml. Free and complexed clofazimine inhibited the growth of MAC inside macrophages to a similar extent, while modified cyclodextrin alone had no observable effects on MAC or macrophages. Complexed clofazimine was not toxic to cells at concentrations effective against MAC. The TD(50) of the modified cyclodextrin in THP-1 cell line was 297 microg/ml.
authors.affiliation: Department of Microbiology, University of the Pacific, 2155 Webster Street, San Francisco, CA 94115, USA. ismail@ugr.es
authors.forename: Isam Ismail
authors.initials: II
authors.lastname: Salem
authors.forename: Gerhard
authors.initials: G
authors.lastname: Steffan
authors.forename: Nejat
authors.initials: N
authors.lastname: Düzgünes
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D002991:Clofazimine / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D013261:Sterols / Q000737:chemistry*; D019802:Succinic Acid / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D013261:Sterols; D019802:Succinic Acid; D002991:Clofazimine