{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:57:17Z","timestamp":1760576237992,"version":"build-2065373602"},"reference-count":30,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class\u2010specific side effects. Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin\u2010resistant <jats:italic>Staphyloccocus aureus<\/jats:italic> (MRSA). Owing to FQ\u2010associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat\u2010dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (<jats:sc>l<\/jats:sc>\u2010arginine salt of levonadifloxacin) and WCK 2349 (<jats:sc>l<\/jats:sc>\u2010alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat\u2010dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea and injection site irritation) and dog (emesis and salivation), no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771\u2010 or WCK 2349\u2010treated groups. WCK 771 and WCK 2349 were found to be nongenotoxic; however, they showed weak phototoxicity that was comparable with levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat\u2010dose administration; however, the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti\u2010MRSA treatment.<\/jats:p>","DOI":"10.1002\/jat.4300","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:43:21Z","timestamp":1644540201000},"page":"1354-1370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Preclinical safety evaluation of levonadifloxacin, a novel anti\u2010methicillin\u2010resistant <i>Staphyloccocus aureus<\/i> benzoquinolizine fluoroquinolone by intravenous and oral administration"],"prefix":"10.1002","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2861-1404","authenticated-orcid":false,"given":"Manohar","family":"Nandanwar","sequence":"first","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atul","family":"Kansagara","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangita","family":"Gupta","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anasuya","family":"Patel","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muftedar Ahmed","family":"Patel","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravindra","family":"Yeole","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak","family":"Thorve","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahesh","family":"Patel","sequence":"additional","affiliation":[{"name":"Wockhardt Research Centre  Aurangabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-2918(00)80053-3"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01150-08"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S229882"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706389"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/c8pp00019k"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867013373435"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.6.1511"},{"key":"e_1_2_7_9_1","unstructured":"FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects.2016.http:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm511530.htm(Accessed on 17 May 2018)"},{"key":"e_1_2_7_10_1","unstructured":"FDA Safety Announcement: FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes. 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