{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T04:31:18Z","timestamp":1719981078366},"reference-count":39,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,29]],"date-time":"2014-11-29T00:00:00Z","timestamp":1417219200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2014,12]]},"abstract":"Summary<\/jats:title>Objective<\/jats:title>2\u2010Ethyl\u20103\u2010methylbutyl\u2010carbamate (EMC<\/jats:styled-content>) and 2\u2010isopropylpentyl\u2010carbamate (IPC<\/jats:styled-content>) are among the most potent anticonvulsant carbamate derivatives of valproic acid. EMC<\/jats:styled-content> and IPC<\/jats:styled-content> are chiral compounds. Consequently, the aim of the current study was to comparatively evaluate the pharmacokinetic (PK<\/jats:styled-content>) and pharmacodynamic (PD<\/jats:styled-content> anticonvulsant activity) profile of EMC<\/jats:styled-content> and IPC<\/jats:styled-content> individual enantiomers.<\/jats:p><\/jats:sec>Methods<\/jats:title>The anticonvulsant activity of EMC<\/jats:styled-content> and IPC<\/jats:styled-content> individual enantiomers was evaluated in several anticonvulsant rodent models including maximal electroshock (MES<\/jats:styled-content>), 6\u00a0Hz psychomotor, subcutaneous (pentylenetetrazole) (scMet), and the pilocarpine\u2010induced and soman\u2010induced status epilepticus (SE<\/jats:styled-content>). The PK<\/jats:styled-content>\u2013PD<\/jats:styled-content> relationship of EMC<\/jats:styled-content> and IPC<\/jats:styled-content> individual enantiomers was evaluated following intraperitoneal administration (50\u00a0mg\/kg) to rats. Induction of neural tube defects (NTD<\/jats:styled-content>s) was evaluated in a mouse strain that was highly susceptible to teratogen\u2010induced NTD<\/jats:styled-content>s.<\/jats:p><\/jats:sec>Results<\/jats:title>In mice and rats, (2S)\u2010EMC<\/jats:styled-content> exhibited anticonvulsant activity similar to that of racemic EMC<\/jats:styled-content> in the MES<\/jats:styled-content> and scMet tests, whereas in the 6\u00a0Hz test, racemic EMC<\/jats:styled-content> was more potent than its two individual enantiomers. Racemic EMC<\/jats:styled-content> exhibited a potent activity in the soman\u2010induced SE<\/jats:styled-content> model when administered 5 and 20\u00a0min after seizure onset with median effective dose (ED<\/jats:styled-content>50<\/jats:sub>) values of 33 and 48\u00a0mg\/kg, respectively. (2R)\u2010IPC<\/jats:styled-content> and (2S)\u2010IPC<\/jats:styled-content> exhibited ED<\/jats:styled-content>50<\/jats:sub> values similar to those of racemic IPC<\/jats:styled-content> in the mouse and rat MES<\/jats:styled-content> and scMet models. (2R)\u2010IPC<\/jats:styled-content> had similar ED<\/jats:styled-content>50<\/jats:sub> values on the 6\u00a0Hz tests. Racemic IPC<\/jats:styled-content> had an ED<\/jats:styled-content>50<\/jats:sub> value of 107\u00a0mg\/kg in the pilocarpine\u2010induced SE<\/jats:styled-content> model when given 30\u00a0min after seizure onset. Racemic EMC<\/jats:styled-content> and IPC<\/jats:styled-content> and their enantiomers had similar clearance (3.8\u20135.5\u00a0L\/h\/kg) and short half\u2010life (<1\u00a0h). EMC<\/jats:styled-content> and its enantiomers did not cause NTDs<\/jats:styled-content> at doses 3\u201310 times higher than their anticonvulsant ED<\/jats:styled-content>50<\/jats:sub> values.<\/jats:p><\/jats:sec>Significance<\/jats:title>EMC<\/jats:styled-content> and IPC<\/jats:styled-content> did not exhibit enantioselective PK<\/jats:styled-content>, a fact that may contribute to their nonenantioselective activity in any of the anticonvulsant models. The nonsignificant difference between racemic EMC<\/jats:styled-content> and racemic IPC<\/jats:styled-content> and their enantiomers, suggests that their wide spectrum of anticonvulsant activity is likely to be caused by multiple mechanisms of action.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12857","type":"journal-article","created":{"date-parts":[[2014,11,29]],"date-time":"2014-11-29T09:19:07Z","timestamp":1417252747000},"page":"1944-1952","source":"Crossref","is-referenced-by-count":7,"title":["Enantioselective pharmacodynamic and pharmacokinetic analysis of two chiral CNS<\/scp>\u2010active carbamate derivatives of valproic acid"],"prefix":"10.1111","volume":"55","author":[{"given":"Tawfeeq","family":"Shekh\u2010Ahmad","sequence":"first","affiliation":[{"name":"Faculty of Medicine Institute for Drug Research School of Pharmacy The Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hafiz","family":"Mawasi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Institute for Drug Research School of Pharmacy The Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John H.","family":"McDonough","sequence":"additional","affiliation":[{"name":"Pharmacology Branch Research Division US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground Maryland U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard H.","family":"Finnell","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences Dell Pediatric Research Institute The University of Texas at Austin Austin Texas U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bogdan J.","family":"Wlodarczyk","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences Dell Pediatric Research Institute The University of Texas at Austin Austin Texas U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eylon","family":"Yavin","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Institute for Drug Research School of Pharmacy The Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meir","family":"Bialer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Institute for Drug Research School of Pharmacy The Hebrew University of Jerusalem Jerusalem Israel"},{"name":"David R. 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