{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T10:50:57Z","timestamp":1758970257280},"reference-count":30,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,2,3]],"date-time":"2009-02-03T00:00:00Z","timestamp":1233619200000},"content-version":"vor","delay-in-days":3778,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[1998,10]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>The objective of this investigation was to determine <jats:italic>quantitatively<\/jats:italic> whether experimental epilepsy is associated with a change in the pharmacodynamics of benzodiazepines <jats:italic>in vivo<\/jats:italic>. For that purpose the pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic\u2010pharmacodynamic approach in three different models of experimental epilepsy: amygdala kindling, cortical stimulation and genetic absence epilepsy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The time course of the EEG effect was determined in conjunction with the decline of drug concentrations after intravenous administration of 10\u2003mg\u2003kg<jats:sup>\u22121<\/jats:sup> midazolam. The pharmacokinetics of midazolam were most adequately described by a bi\u2010exponential equation. No influence of epilepsy on the pharmacokinetics of midazolam was observed.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The increase in \u03b2 activity (11.5\u201330\u2003Hz) of the EEG as derived by Fast Fourier Transformation analysis was used as pharmacodynamic endpoint. For each individual rat the increase in \u03b2 activity was directly related to the concentration in blood on the basis of the sigmoidal E<jats:sub>max<\/jats:sub> pharmacodynamic model. In all three models a significant reduction in the maximal effect was observed, in amygdala kindling 28%, in the cortical stimulation model 49% and in genetic absence epilepsy 37%. No differences in the other pharmacodynamic parameters, E<jats:sub>0<\/jats:sub>, EC<jats:sub>50,u<\/jats:sub> and Hill factor, were observed.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>It is inferred that in three different models of epilepsy there is a similar change in GABAergic functioning which is associated with a significant reduction in the intrinsic activity of midazolam <jats:italic>in vivo<\/jats:italic>. These models provide therefore a useful basis for further studies on the mechanism of epilepsy\u2010induced changes in pharmacodynamics of anti\u2010epileptic drugs.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (1998) <jats:bold>125<\/jats:bold>, 615\u2013620; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0702088\">10.1038\/sj.bjp.0702088<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0702088","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T19:50:22Z","timestamp":1106941822000},"page":"615-620","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Adaptive changes in the pharmacodynamics of midazolam in different experimental models of epilepsy: kindling, cortical stimulation and genetic absence epilepsy"],"prefix":"10.1111","volume":"125","author":[{"given":"A","family":"Cleton","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R A","family":"Voskuyl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Danhof","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01062959"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1983.0093"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(87)90005-2"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90875-A"},{"key":"e_1_2_6_6_1","first-page":"339","article-title":"Log\u2010normal distribution of equieffective doses of norepinephrine and acetylcholine in several tissues","volume":"181","author":"Flemming W.W.","year":"1972","journal-title":"J. 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