{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:29:02Z","timestamp":1787016542897,"version":"build-2736575974"},"reference-count":41,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The repurposing of existing drugs is being pursued as a means by which to accelerate the development of novel regimens for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). In the current study, we assessed the activity of the antipsychotic drug thioridazine (TRZ) in combination with the standard regimen in a well-validated murine TB model. Single-dose and steady-state pharmacokinetic studies were performed in BALB\/c mice to establish human-equivalent doses of TRZ. To determine the bactericidal activity of TRZ against TB in BALB\/c mice, three separate studies were performed, including a dose-ranging study of TRZ monotherapy and efficacy studies of human-equivalent doses of TRZ with and without isoniazid (INH) or rifampin (RIF). Therapeutic efficacy was assessed by the change in mycobacterial load in the lung. The human-equivalent dose of thioridazine was determined to be 25 mg\/kg of body weight, which was well tolerated in mice. TRZ was found to accumulate at high concentrations in lung tissue relative to serum levels. We observed modest synergy during coadministration of TRZ with INH, and the addition of TRZ reduced the emergence of INH-resistant mutants in mouse lungs. In conclusion, this study further illustrates the opportunity to reevaluate the contribution of TRZ to the sterilizing activity of combination regimens to prevent the emergence of drug-resistant\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n                    .\n                  <\/jats:p>","DOI":"10.1128\/aac.02981-14","type":"journal-article","created":{"date-parts":[[2014,5,5]],"date-time":"2014-05-05T23:36:16Z","timestamp":1399332976000},"page":"4048-4053","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":34,"title":["Reduced Emergence of Isoniazid Resistance with Concurrent Use of Thioridazine against Acute Murine Tuberculosis"],"prefix":"10.1128","volume":"58","author":[{"given":"Noton K.","family":"Dutta","sequence":"first","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Pinn","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petros C.","family":"Karakousis","sequence":"additional","affiliation":[{"name":"Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"name":"Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(13)70030-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-009-0739-z"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4103\/0255-0857.99481"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201011-1924OC"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.12.0616"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20020615"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.8.3175-3178.2004"},{"key":"e_1_3_2_9_2","first-page":"751","article-title":"Non-antibiotics reverse resistance of bacteria to antibiotics","volume":"24","author":"Kristiansen JE","year":"2010","unstructured":"KristiansenJEThomsenVFMartinsAViveirosMAmaralL. 2010. Non-antibiotics reverse resistance of bacteria to antibiotics. In Vivo 24:751\u2013754. http:\/\/iv.iiarjournals.org\/content\/24\/5\/751.long.","journal-title":"In Vivo"},{"key":"e_1_3_2_10_2","first-page":"69","article-title":"Inhibitors of Ca2+ and K+ transport enhance intracellular killing of M. tuberculosis by non-killing macrophages","volume":"22","author":"Martins M","year":"2008","unstructured":"MartinsMViveirosMAmaralL. 2008. Inhibitors of Ca2+ and K+ transport enhance intracellular killing of M. tuberculosis by non-killing macrophages. In Vivo 22:69\u201375. http:\/\/iv.iiarjournals.org\/content\/22\/1\/69.full.pdf+html.","journal-title":"In Vivo"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkl500"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.022"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02293-13"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.2174\/157489111796064533"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2009.12.019"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.2174\/157489111796064588"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/157489111796064597"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010069"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0034538"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508844200"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-8579(00)00343-5"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2009.02.015"},{"key":"e_1_3_2_23_2","first-page":"771","article-title":"The curative activity of thioridazine on mice infected with Mycobacterium tuberculosis","volume":"21","author":"Martins M","year":"2007","unstructured":"MartinsMViveirosMKristiansenJEMolnarJAmaralL. 2007. The curative activity of thioridazine on mice infected with Mycobacterium tuberculosis. In Vivo 21:771\u2013775. http:\/\/iv.iiarjournals.org\/content\/21\/5\/771.full.pdf+html.","journal-title":"In Vivo"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012640"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr500"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.2174\/157489111796064551"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.3.917-922.2003"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt037"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00500-12"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01933-12"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00495864"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01524-10"},{"key":"e_1_3_2_33_2","unstructured":"Reference deleted."},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00912-12"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600781003"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/35016103"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkq007"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn070"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.7.2415-2423.2004"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.9.2804-2810.2002"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00829-13"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku036"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02981-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02981-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T17:48:56Z","timestamp":1645465736000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02981-14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7]]},"references-count":41,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2014,7]]}},"alternative-id":["10.1128\/AAC.02981-14"],"URL":"https:\/\/doi.org\/10.1128\/aac.02981-14","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7]]},"assertion":[{"value":"2014-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-04-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}