{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:06:55Z","timestamp":1781510815470,"version":"3.54.1"},"reference-count":72,"publisher":"Wiley","issue":"s8","license":[{"start":{"date-parts":[[2012,12,3]],"date-time":"2012-12-03T00:00:00Z","timestamp":1354492800000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism\u2010unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative\u2010hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.<\/jats:p>","DOI":"10.1111\/epi.12024","type":"journal-article","created":{"date-parts":[[2012,12,4]],"date-time":"2012-12-04T07:39:06Z","timestamp":1354606746000},"page":"3-11","source":"Crossref","is-referenced-by-count":27,"title":["How did phenobarbital\u2019s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?"],"prefix":"10.1111","volume":"53","author":[{"given":"Meir","family":"Bialer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,12,3]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"496","volume-title":"Antiepileptic drugs","author":"Anderson GD","year":"2002"},{"key":"e_1_2_12_3_1","first-page":"371","volume-title":"Antiepileptic drugs","author":"Anderson GD","year":"1995"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4637.2011.01139.x"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-5618.2010.00828.x"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199120020-00003"},{"key":"e_1_2_12_7_1","first-page":"459","volume-title":"Antiepileptic drugs","author":"Bialer M","year":"2002"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.15.6.637"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02348.x"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2011.11.006"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2012.03519.x"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2997"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nurt.2006.11.007"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2004.08.021"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2008.09.005"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2010.09.001"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cber.190804101255"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1122960"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1953.tb00784.x"},{"key":"e_1_2_12_20_1","first-page":"449","volume-title":"Antiepileptic drugs","author":"Bourgeois BFD","year":"1995"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.33.3.283"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.33.3.291"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1985.tb02800.x"},{"key":"e_1_2_12_24_1","first-page":"385","article-title":"On the propyl derivatives and decomposition of ethylaceto\u2010acetate","volume":"3","author":"Burton BS","year":"1882","journal-title":"Am Chem J"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-93-22813"},{"key":"e_1_2_12_26_1","first-page":"468","article-title":"Properties pharmamcodynamiques de l\u2019acide n\u2010dipropylacetique et ses derives","volume":"19","author":"Carraz G","year":"1964","journal-title":"Therapy"},{"key":"e_1_2_12_27_1","first-page":"210","article-title":"New antiepileptic in the treatment of epilepsy (3\u2010methyl\u20105,5\u2010phenyl\u2010hydantoin) (Hydantal) Preliminary report","volume":"44","author":"Clein NW","year":"1945","journal-title":"Northwest Med"},{"key":"e_1_2_12_28_1","first-page":"176","article-title":"Cemisch\u2010Historische Aanteel keningen. 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