{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:13:44Z","timestamp":1777493624533,"version":"3.51.4"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,12,6]],"date-time":"2013-12-06T00:00:00Z","timestamp":1386288000000},"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":[[2014,2]]},"abstract":"Summary<\/jats:title>Objective<\/jats:title>Valnoctamide (VCD<\/jats:styled-content>), a central nervous system (CNS<\/jats:styled-content>)\u2013active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA<\/jats:styled-content>), is currently undergoing phase II<\/jats:styled-content>b clinical trials in acute mania. VCD<\/jats:styled-content> exhibits stereoselective pharmacokinetics (PK<\/jats:styled-content>) in animals and humans. The current study comparatively evaluated the pharmacodynamics (PD<\/jats:styled-content>; anticonvulsant activity and teratogenicity) and PK<\/jats:styled-content> of the four individual stereoisomers of VCD<\/jats:styled-content>.<\/jats:p><\/jats:sec>Methods<\/jats:title>The anticonvulsant activity of VCD<\/jats:styled-content> individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6\u00a0Hz psychomotor, subcutaneous metrazol, and the pilocarpine\u2010induced and soman\u2010induced status epilepticus (SE<\/jats:styled-content>). The PK<\/jats:styled-content>\u2010PD<\/jats:styled-content> (anticonvulsant activity) relationship of VCD<\/jats:styled-content> stereoisomers was evaluated following intraperitoneal administration (70\u00a0mg\/kg) to rats. Induction of neural tube defects (NTD<\/jats:styled-content>s) by VCD<\/jats:styled-content> stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen\u2010induced NTDs.<\/jats:p><\/jats:sec>Results<\/jats:title>VCD<\/jats:styled-content> had a stereoselective PK<\/jats:styled-content>, with (2S,3S)\u2010VCD<\/jats:styled-content> exhibiting the lowest clearance, and consequently a twice\u2010higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD<\/jats:styled-content> anticonvulsant activity and each stereoisomer had similar median effective dose (ED<\/jats:styled-content>)50<\/jats:sub> values in most models. VCD<\/jats:styled-content> stereoisomers (258 or 389\u00a0mg\/kg) did not cause NTD<\/jats:styled-content>s. These doses are 3\u201312 times higher than VCD<\/jats:styled-content> anticonvulsant ED<\/jats:styled-content>50<\/jats:sub> values.<\/jats:p><\/jats:sec>Significance<\/jats:title>VCD<\/jats:styled-content> displayed stereoselective PK<\/jats:styled-content> that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD<\/jats:styled-content> exerted its broad\u2010spectrum anticonvulsant activity using a single mechanism of action (MOA<\/jats:styled-content>), it is likely that it would exhibit a stereoselective PD<\/jats:styled-content>. The fact that there was no significant difference between racemic VCD<\/jats:styled-content> and its individual stereoisomers suggests that VCD<\/jats:styled-content>'s anticonvulsant activity is due to multiple MOA<\/jats:styled-content>s.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12480","type":"journal-article","created":{"date-parts":[[2013,12,6]],"date-time":"2013-12-06T23:50:52Z","timestamp":1386373852000},"page":"353-361","source":"Crossref","is-referenced-by-count":24,"title":["Stereoselective anticonvulsant and pharmacokinetic analysis of valnoctamide, a CNS<\/scp>\u2010active derivative of valproic acid with low teratogenic potential"],"prefix":"10.1111","volume":"55","author":[{"given":"Tawfeeq","family":"Shekh\u2010Ahmad","sequence":"first","affiliation":[{"name":"Faculty of Medicine School of Pharmacy Institute for Drug Research The Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naama","family":"Hen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine School of Pharmacy Institute for Drug Research The Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boris","family":"Yagen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine School of Pharmacy Institute for Drug Research The Hebrew University of Jerusalem Jerusalem Israel"},{"name":"David R. Bloom Center for 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":"Meir","family":"Bialer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine School of Pharmacy Institute for Drug Research The Hebrew University of Jerusalem Jerusalem Israel"},{"name":"David R. 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