In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: Insights into the mechanisms of pharmacoresistance
Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentratio...
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| Veröffentlicht in: | Brain research 2006-05, Vol.1086 (1), p.201-213 |
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| creator | Oby, Emily Caccia, Silvio Vezzani, Annamaria Moeddel, Gabriel Hallene, Kerri Guiso, Giovanna Said, Tamer Bingaman, William Marchi, Nicola Baumgartner, Christoph Pirker, Susanne Czech, Thomas Lo Russo, Giorgio Janigro, Damir |
| description | Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15–34 μM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg
2+-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60–200 μM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system. |
| doi_str_mv | 10.1016/j.brainres.2006.02.068 |
| format | Article |
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2+-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60–200 μM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.</description><identifier>ISSN: 0006-8993</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/j.brainres.2006.02.068</identifier><identifier>PMID: 16631625</identifier><identifier>CODEN: BRREAP</identifier><language>eng</language><publisher>London: Elsevier B.V</publisher><subject>Adolescent ; Adult ; Aged ; Animals ; Anticonvulsants - administration & dosage ; Anticonvulsants - blood ; Anticonvulsants - cerebrospinal fluid ; Anticonvulsants. Antiepileptics. Antiparkinson agents ; Biological and medical sciences ; Brain - drug effects ; Brain - metabolism ; Brain development ; Child ; Child, Preschool ; Chromatography, High Pressure Liquid - methods ; Cortical dysplasia ; Drug Resistance ; Drug transport ; Epilepsy - drug therapy ; Epilepsy - physiopathology ; Female ; Humans ; In Vitro Techniques ; Infant ; Male ; Medical sciences ; Membrane Potentials - drug effects ; Membrane Potentials - physiology ; Membrane Potentials - radiation effects ; Mice ; Middle Aged ; Neuropharmacology ; P-glycoprotein ; Patch-Clamp Techniques - methods ; Pharmacokinetic ; Pharmacology. Drug treatments ; Potassium Chloride - pharmacology ; Rats</subject><ispartof>Brain research, 2006-05, Vol.1086 (1), p.201-213</ispartof><rights>2006 Elsevier B.V.</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-928c85bbe36b91cb97174857e34ac6035a8ed5079bb4fcd208453341f1d48cf23</citedby><cites>FETCH-LOGICAL-c427t-928c85bbe36b91cb97174857e34ac6035a8ed5079bb4fcd208453341f1d48cf23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.brainres.2006.02.068$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17785490$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16631625$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oby, Emily</creatorcontrib><creatorcontrib>Caccia, Silvio</creatorcontrib><creatorcontrib>Vezzani, Annamaria</creatorcontrib><creatorcontrib>Moeddel, Gabriel</creatorcontrib><creatorcontrib>Hallene, Kerri</creatorcontrib><creatorcontrib>Guiso, Giovanna</creatorcontrib><creatorcontrib>Said, Tamer</creatorcontrib><creatorcontrib>Bingaman, William</creatorcontrib><creatorcontrib>Marchi, Nicola</creatorcontrib><creatorcontrib>Baumgartner, Christoph</creatorcontrib><creatorcontrib>Pirker, Susanne</creatorcontrib><creatorcontrib>Czech, Thomas</creatorcontrib><creatorcontrib>Lo Russo, Giorgio</creatorcontrib><creatorcontrib>Janigro, Damir</creatorcontrib><title>In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: Insights into the mechanisms of pharmacoresistance</title><title>Brain research</title><addtitle>Brain Res</addtitle><description>Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15–34 μM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg
2+-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60–200 μM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Anticonvulsants - administration & dosage</subject><subject>Anticonvulsants - blood</subject><subject>Anticonvulsants - cerebrospinal fluid</subject><subject>Anticonvulsants. Antiepileptics. Antiparkinson agents</subject><subject>Biological and medical sciences</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain development</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Chromatography, High Pressure Liquid - methods</subject><subject>Cortical dysplasia</subject><subject>Drug Resistance</subject><subject>Drug transport</subject><subject>Epilepsy - drug therapy</subject><subject>Epilepsy - physiopathology</subject><subject>Female</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Infant</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Potentials - drug effects</subject><subject>Membrane Potentials - physiology</subject><subject>Membrane Potentials - radiation effects</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Neuropharmacology</subject><subject>P-glycoprotein</subject><subject>Patch-Clamp Techniques - methods</subject><subject>Pharmacokinetic</subject><subject>Pharmacology. 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Antiepileptics. Antiparkinson agents</topic><topic>Biological and medical sciences</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Brain development</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Chromatography, High Pressure Liquid - methods</topic><topic>Cortical dysplasia</topic><topic>Drug Resistance</topic><topic>Drug transport</topic><topic>Epilepsy - drug therapy</topic><topic>Epilepsy - physiopathology</topic><topic>Female</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Infant</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Potentials - drug effects</topic><topic>Membrane Potentials - physiology</topic><topic>Membrane Potentials - radiation effects</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Neuropharmacology</topic><topic>P-glycoprotein</topic><topic>Patch-Clamp Techniques - methods</topic><topic>Pharmacokinetic</topic><topic>Pharmacology. 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Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15–34 μM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg
2+-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60–200 μM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.</abstract><cop>London</cop><cop>Amsterdam</cop><cop>New York, NY</cop><pub>Elsevier B.V</pub><pmid>16631625</pmid><doi>10.1016/j.brainres.2006.02.068</doi><tpages>13</tpages></addata></record> |
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| subjects | Adolescent Adult Aged Animals Anticonvulsants - administration & dosage Anticonvulsants - blood Anticonvulsants - cerebrospinal fluid Anticonvulsants. Antiepileptics. Antiparkinson agents Biological and medical sciences Brain - drug effects Brain - metabolism Brain development Child Child, Preschool Chromatography, High Pressure Liquid - methods Cortical dysplasia Drug Resistance Drug transport Epilepsy - drug therapy Epilepsy - physiopathology Female Humans In Vitro Techniques Infant Male Medical sciences Membrane Potentials - drug effects Membrane Potentials - physiology Membrane Potentials - radiation effects Mice Middle Aged Neuropharmacology P-glycoprotein Patch-Clamp Techniques - methods Pharmacokinetic Pharmacology. Drug treatments Potassium Chloride - pharmacology Rats |
| title | In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: Insights into the mechanisms of pharmacoresistance |
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