{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:03:27Z","timestamp":1789614207046,"version":"build-2803163510"},"reference-count":25,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"VA Merit award","award":["BX002006"],"award-info":[{"award-number":["BX002006"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI140287-06"],"award-info":[{"award-number":["R01AI140287-06"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,8,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Glycopeptide, polymyxin, and aminoglycoside antibiotics are among the most commonly used agents to treat drug-resistant bacterial infections; however, their clinical use is hindered by nephrotoxicity. We previously reported that zileuton has the potential to attenuate antibiotic-associated nephrotoxicity in an animal model. Here, we further report the development of a parenteral formulation and exploration of dosing strategies for zileuton. The solubility, stability, and multi-dose safety of two zileuton formulations were evaluated. Zileuton serum and renal tissue pharmacokinetics were evaluated after a single dose and compared to steady state after 10 days. Different dosing strategies of zileuton to attenuate vancomycin-, polymyxin B-, and amikacin-associated nephrotoxicity were evaluated in rats over 10 days. Two formulations (1 and 10 mg\/mL) showed good multi-dose safety, with no significant changes in serum creatinine, alanine transaminase, or body weight observed following doses of 12 mg\/kg daily for 10 days. Zileuton was well-distributed into renal tissue, and serum exposure was comparable to humans after a typical dose (600\u20132,400 mg). No drug accumulation at steady state was observed. Zileuton was found to reduce nephrotoxicity associated with vancomycin, polymyxin B, and amikacin in a dose-dependent manner. With the same daily dose, dose fractionation resulted in similar renal protection compared to once-daily dosing. These preliminary studies support that zileuton has the potential to be used as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity. This would allow the optimal use of glycopeptides, polymyxins, and aminoglycosides to treat difficult infections. Further studies are warranted to repurpose zileuton as a nephroprotectant.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00287-25","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T09:56:17Z","timestamp":1751968577000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Drug development studies supporting zileuton as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity"],"prefix":"10.1128","volume":"69","author":[{"given":"Cole S.","family":"Hudson","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacological & Pharmaceutical Sciences, University of Houston College of Pharmacy","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Smith","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice & Translational Research, University of Houston College of Pharmacy","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh T.","family":"Vuong","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice & Translational Research, University of Houston College of Pharmacy","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas S.","family":"Teran","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice & Translational Research, University of Houston College of Pharmacy","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazanin","family":"Pouya","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice & Translational Research, University of Houston College of Pharmacy","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sheikh-Hamad","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Nephrology and Selzman Institute for Kidney Health, Department of Medicine, Baylor College of Medicine","place":["Houston, USA"]},{"id":[{"id":"https:\/\/ror.org\/052qqbc08","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Translational Research on Inflammatory Diseases (CTRID), Michael E DeBakey VA Medical Center","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinli","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacological & Pharmaceutical Sciences, University of Houston College of Pharmacy","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shama","family":"Kajiji","sequence":"additional","affiliation":[{"name":"Emergent System Analytics, LLC","place":["Clinton, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7071-5376","authenticated-orcid":true,"given":"Vincent H.","family":"Tam","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacological & Pharmaceutical Sciences, University of Houston College of Pharmacy","place":["Houston, USA"]},{"id":[{"id":"https:\/\/ror.org\/048sx0r50","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy Practice & Translational Research, University of Houston College of Pharmacy","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","unstructured":"CDC. 2024. 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