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We examined time-kill curves of thioridazine and first-line drugs against log-growth-phase and semidormant bacilli under acidic conditions and nonreplicating persistent\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n            . While both the potency and the efficacy of first-line drugs declined dramatically as\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            replication rates decreased, those of thioridazine improved. The mutation prevalence to 3 times the thioridazine MIC was &lt;1 \u00d7 10\n            <jats:sup>\u221211<\/jats:sup>\n            , better than for \u22652 first-line drugs combined. Hollow fiber system studies revealed that the relationship between sterilizing effect and pharmacodynamic indices (PDI) was characterized by an\n            <jats:italic>r<\/jats:italic>\n            <jats:sup>2<\/jats:sup>\n            of 0.88 for peak\/MIC, an\n            <jats:italic>r<\/jats:italic>\n            <jats:sup>2<\/jats:sup>\n            of 0.47 for the area under the concentration-time curve (AUC) to MIC, and an\n            <jats:italic>r<\/jats:italic>\n            <jats:sup>2<\/jats:sup>\n            of 0.14 for the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%\n            <jats:italic>T<\/jats:italic>\n            <jats:sub>MIC<\/jats:sub>\n            ) at the end of the first week. However, the PDI linked to effect \u201cwobbled\u201d as the duration of therapy increased, so that by the fourth week the\n            <jats:italic>r<\/jats:italic>\n            <jats:sup>2<\/jats:sup>\n            was 0.88 for AUC\/MIC, 0.78 for %T\n            <jats:sub>MIC<\/jats:sub>\n            , and 0.72 for peak\/MIC. This \u201cwobble\u201d has implications on general pharmacokinetic\/pharmacodynamic theory, whereby efficacy is linked to only one of the three PDIs in deterministic models. The potency changed 8.9-fold from the first to the fourth weeks. The non-protein-bound AUC\/MIC associated with maximal kill at the end of therapy was 50.53 (protein binding = 99.5%). This thioridazine exposure was calculated to extinguish all three\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            metabolic populations in human lungs in only 42.9 days of monotherapy. However, this concentration exceeds the 2- to 8-mg\/liter thioridazine concentration in serum known to be lethal to humans. Therefore, the way forward for phenothiazine monotherapy that also reduces therapy duration is via synthesis of less toxic congeners.\n          <\/jats:p>","DOI":"10.1128\/aac.00829-13","type":"journal-article","created":{"date-parts":[[2013,9,17]],"date-time":"2013-09-17T03:45:54Z","timestamp":1379389554000},"page":"5870-5877","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["Thioridazine Pharmacokinetic-Pharmacodynamic Parameters \u201cWobble\u201d during Treatment of Tuberculosis: a Theoretical Basis for Shorter-Duration Curative Monotherapy with Congeners"],"prefix":"10.1128","volume":"57","author":[{"given":"Sandirai","family":"Musuka","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashikant","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA"},{"name":"Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandima Wasana","family":"Siyambalapitiyage Dona","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Meek","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Leff","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jotam","family":"Pasipanodya","sequence":"additional","affiliation":[{"name":"Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tawanda","family":"Gumbo","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA"},{"name":"Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106753"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808427"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60333-0"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01354-09"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir658"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis353"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit167"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit352"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60734-X"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61069-1"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108789"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir889"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis128"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00136312"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1903.120246"},{"key":"e_1_3_2_17_2","first-page":"59","article-title":"Recherches sur les dim\u00e9thylaminopropyl-N ph\u00e9nothiazines substitu\u00e9es","volume":"235","author":"Charpentier P","year":"1952","unstructured":"CharpentierP GailliotP JacobsR. 1952. 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