{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T08:33:32Z","timestamp":1767861212093,"version":"3.49.0"},"reference-count":65,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2006,10,26]],"date-time":"2006-10-26T00:00:00Z","timestamp":1161820800000},"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":[[2006,11]]},"abstract":"<jats:p><jats:bold>Summary:\u2002<\/jats:bold><jats:italic>Purpose:<\/jats:italic>Isobolographic analysis was used to characterize the interactions between stiripentol (STP) and clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)\u2010induced clonic seizures in mice.<\/jats:p><jats:p><jats:italic>Methods:<\/jats:italic>The anticonvulsant and acute adverse (neurotoxic) effects of STP in combination with the various conventional antiepileptic drugs (AEDs), at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the PTZ and chimney tests in mice using the isobolographic analysis. Additionally, protective indices (PI) and benefit indices (BI) were calculated to identify their pharmacological profiles so that a ranking in relation to advantageous combination could be established. Moreover, adverse\u2010effect paradigms were determined by use of the step\u2010through passive avoidance task (long\u2010term memory), threshold for the first pain reaction, grip\u2010strength test (neuromuscular tone), and the hot plate test (acute thermal pain). Brain AED concentrations were also measured so as to ascertain any pharmacokinetic contribution to the pharmacodynamic interactions.<\/jats:p><jats:p><jats:italic>Results:<\/jats:italic>All AED combinations comprising of STP and CZP, ETS, PB, and VPA (at the fixed ratios of 1:3, 1:1 and 3:1) were additive in terms of clonic seizure suppression in the PTZ test. However, these interactions were complicated by changes in brain AED concentrations consequent to pharmacokinetic interactions. Thus STP significantly increased total brain ETS and PB concentrations, and decreased VPA concentrations, but was without effect on CZP concentrations. In contrast, PB significantly decreased and VPA increased total brain STP concentrations while CZP and ETS were without effect. Furthermore, while isobolographic analysis revealed that STP and CZP in combination, at the fixed ratios of 1:1 and 3:1, were supraadditive (synergistic; p &lt; 0.05), the combinations of STP with CZP (1:3), ETS, PB, or VPA (at all fixed ratios of 1:3, 1:1, and 3:1) were barely additivity in terms of acute neurotoxic adverse effects in the chimney test. Additionally, none of the examined combinations of STP with conventional AEDs (CZP, ETS, PB, VPA\u2014at their median effective doses from the PTZ\u2010test) affected long\u2010term memory, threshold for the first pain reaction, neuromuscular tone, and acute thermal pain.<\/jats:p><jats:p><jats:italic>Conclusions:<\/jats:italic>Based on BI values, the combination of STP with PB at the fixed ratio of 1:3 appears to be a particularly favourable combination. In contrast, STP and CZP or ETS (at the fixed ratios of 1:1 and 3:1) were unfavorable combinations. However, these conclusions are confounded by the fact that STP is associated with significant pharmacokinetic interactions. The remaining combinations of STP with PB (1:1 and 3:1), CZP (1:3), ETS (1:3), and VPA (at all fixed ratios of 1:3, 1:1, and 3:1) do not appear to be potential favorable AED combinations.<\/jats:p>","DOI":"10.1111\/j.1528-1167.2006.00825.x","type":"journal-article","created":{"date-parts":[[2006,10,26]],"date-time":"2006-10-26T15:55:01Z","timestamp":1161878101000},"page":"1841-1854","source":"Crossref","is-referenced-by-count":25,"title":["Characterization of the Anticonvulsant, Behavioral and Pharmacokinetic Interaction Profiles of Stiripentol in Combination with Clonazepam, Ethosuximide, Phenobarbital, and Valproate Using Isobolographic Analysis"],"prefix":"10.1111","volume":"47","author":[{"given":"Jarogniew J.","family":"Luszczki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neville","family":"Ratnaraj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip N.","family":"Patsalos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislaw J.","family":"Czuczwar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,10,26]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.59.5_suppl_2.S14"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199448020-00003"},{"key":"e_1_2_6_4_1","first-page":"93","article-title":"What is synergy","volume":"41","author":"Berenbaum MC","year":"1989","journal-title":"Pharmacol Rev"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000134913"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0306-5251.2003.01919.x"},{"issue":"6","key":"e_1_2_6_7_1","first-page":"73","article-title":"Multifocal epilepsy in infancy: value of stiripentol\u2010clonazepam combination","volume":"34","author":"Chiron C","year":"1993","journal-title":"Epilepsia"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)03157-3"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.2000.tb00111.x"},{"key":"e_1_2_6_10_1","first-page":"385","article-title":"Synthetic analgesics. II. Dithienylbutenyl\u2010 and dithienylbutylamines","volume":"107","author":"Eddy NB","year":"1953","journal-title":"J Pharmacol Exp Ther"},{"issue":"3","key":"e_1_2_6_11_1","first-page":"81","article-title":"Stiripentol shows promise in partial complex seizures in children","volume":"33","author":"Farwell J","year":"1992","journal-title":"Epilepsia"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1993.tb02416.x"},{"key":"e_1_2_6_13_1","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/S0022-3565(24)35017-7","article-title":"Preclinical evaluation of newly approved and potential antiepileptic drugs against cocaine\u2010induced seizures","volume":"290","author":"Gasior M","year":"1999","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.007237"},{"key":"e_1_2_6_15_1","first-page":"331","article-title":"The search for synergy: a critical review from a response surface perspective","volume":"47","author":"Greco WR","year":"1995","journal-title":"Pharmacol Rev"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/seiz.2001.0594"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1991.tb05254.x"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.9.4.685"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200002033420503"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1053\/seiz.2000.0442"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1984.237"},{"key":"e_1_2_6_22_1","first-page":"605","article-title":"Effects of stiripentol on valproate plasma level and metabolism","volume":"28","author":"Levy RH","year":"1987","journal-title":"Epilepsia"},{"key":"e_1_2_6_23_1","first-page":"99","article-title":"A simplified method of evaluating dose\u2010effect experiments","volume":"96","author":"Litchfield JT","year":"1949","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1985.tb05715.x"},{"key":"e_1_2_6_25_1","first-page":"618","article-title":"Randomized double\u2010blind, parallel, multicenter trial of stiripentol added to carbamazepine in the treatment of carbamazepine\u2010resistant epilepsies: an interim analysis","volume":"31","author":"Loiseau P","year":"1990","journal-title":"Epilepsia"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(91)90062-K"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(89)90389-0"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(91)90041-D"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(88)90054-X"},{"issue":"11","key":"e_1_2_6_30_1","first-page":"61","article-title":"Use of animal models in developing guiding principles for polypharmacy in epilepsy","author":"L\u00f6scher W","year":"1996","journal-title":"Epilepsy Res"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2003.08.003"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-004-0867-z"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.32702.x"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.10003.x"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2005.07.007"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0013-9580.2005.34704.x"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-006-0055-4"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300243"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300602"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-004-0865-1"},{"key":"e_1_2_6_41_1","first-page":"673","article-title":"Clinical antiepileptic efficacy of stiripentol in resistant partial epilepsies","volume":"25","author":"Martinez\u2010Lage JM","year":"1984","journal-title":"Epilepsia"},{"key":"e_1_2_6_42_1","first-page":"709","article-title":"Effect of stiripentol on petit mal\u2010like epilepsy in Wistar rats","volume":"29","author":"Micheletti G","year":"1988","journal-title":"Epilepsia"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02292767"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2002.13001.x"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(03)00409-5"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb02048.x"},{"key":"e_1_2_6_47_1","first-page":"913","volume-title":"Antiepileptic drugs","author":"Perucca E","year":"2002"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1998.tb01268.x"},{"issue":"162","key":"e_1_2_6_49_1","first-page":"31","article-title":"Pharmacological principles as a basis for polytherapy","author":"Perucca E","year":"1995","journal-title":"Acta Neurol Scand"},{"key":"e_1_2_6_50_1","first-page":"199","article-title":"A new type of anticonvulsant, stiripentol. Pharmacological profile and neurochemical study","volume":"34","author":"Poisson M","year":"1984","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(90)90190-H"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2006.00497.x"},{"issue":"6","key":"e_1_2_6_53_1","first-page":"74","article-title":"Single\u2010blind add\u2010on trial of stiripentol in epileptic children","volume":"34","author":"Renard F","year":"1993","journal-title":"Epilepsia"},{"issue":"7","key":"e_1_2_6_54_1","first-page":"112","article-title":"Stiripentol potentiates clobazam in childhood epilepsy: a pharmacological study","volume":"40","author":"Rey E","year":"1999","journal-title":"Epilepsia"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1059-1311(96)80111-7"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(90)90052-W"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(92)90088-B"},{"key":"e_1_2_6_58_1","first-page":"341","article-title":"Tiagabine for treating painful tonic spasms in multiple sclerosis: a pilot study","volume":"75","author":"Solaro C","year":"2004","journal-title":"J Neurol, Neurosurg Psychiatr"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1053\/seiz.2002.0711"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(01)02195-4"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1201\/9781420036107"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ajp.0000110637.14355.77"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(97)90044-8"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/321864a0"},{"key":"e_1_2_6_65_1","first-page":"455","article-title":"Pharmaco\u2010cellular enzymology of the mechanism of action of stiripentol in cardiazol\u2010induced epilepsy. III. Protein, nucleoprotein, lipid, and proteoglycan metabolism","volume":"23","author":"Wegmann R","year":"1978","journal-title":"Cell Mol Biol Incl Cyto-Enzymol"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1528-1167.2006.00825.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1528-1167.2006.00825.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T17:56:31Z","timestamp":1736618191000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1528-1167.2006.00825.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,10,26]]},"references-count":65,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2006,11]]}},"alternative-id":["10.1111\/j.1528-1167.2006.00825.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1528-1167.2006.00825.x","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,10,26]]}}}