title: Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy.
abstract: The in vitro and in vivo anti-mycobacterial activities of a number of phenothiazine compounds are reviewed. These compounds, normally employed for the management of psychosis, inhibit the growth in vitro of Mycobacterium tuberculosis at concentrations that are significantly greater than those that can safely be achieved in a patient harbouring these infections. Nevertheless, one of these phenothiazines, chlorpromazine, is concentrated by human macrophages to 10-100 times its concentration in plasma, and has activity against mycobacteria that have been phagocytosed by these cells. Phenothiazines have significant in vitro activity against susceptible, polydrug- and multidrug-resistant strains of M. tuberculosis, as well as enhancing the activity of some agents employed for first-line treatment. Because thioridazine, the very mild anti-psychotic agent whose most common side effect is drowsiness, has equal anti-tuberculosis properties in vitro to chlorpromazine, we recommend that thioridazine be studied as an adjuvant to the four- or five-drug regimens employed for the management of a freshly diagnosed tuberculosis infection of unknown antibiotic susceptibility, at least during the period required for the assessment of antibiotic susceptibility. Because it also enhances the activity of rifampicin and streptomycin, antibiotics that frequently have adverse effects, additional studies evaluating the use of thioridazine as an adjuvant may eventually allow a reduction in the dosages of these antibiotics and result in a decreased frequency of adverse effects. It is important to note that whereas the management of patients with thioridazine for periods in excess of many months will result in the appearance of some undesirable side effects, its use for a limited period of 2-3 months should not produce side effects that are more severe than simple drowsiness. Nevertheless, further in vitro and in vivo studies are essential before thioridazine may be recommended for the management of select cases of pulmonary tuberculosis.
authors.affiliation: Unit of Mycobacteriology, Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa, Lisbon, Portugal. lamaral@ihmt.unl.pt
authors.forename: L
authors.initials: L
authors.lastname: Amaral
authors.forename: J E
authors.initials: JE
authors.lastname: Kristiansen
authors.forename: M
authors.initials: M
authors.lastname: Viveiros
authors.forename: J
authors.initials: J
authors.lastname: Atouguia
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013881:Thioridazine / Q000494:pharmacology* / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology
chemical_list: D014150:Antipsychotic Agents; D000995:Antitubercular Agents; D013881:Thioridazine