title: Nanoparticle formulation improves the anticonvulsant effect of clonazepam on the pentylenetetrazole-induced seizures: behavior and electroencephalogram.
abstract: To document the efficacy of clonazepam (CLZ) either free as a solution or loaded in solid lipid nanoparticles (CLZ-SLN) or mixed micelles (CLZ-MM), the in vitro blood-brain barrier permeability of the formulations was determined. Behavior and/or electroencephalograms (EEGs) of rodents receiving treatments were also studied. The in vitro permeability of CLZ increased when associated with SLN, but decreased in the case of MM. The occurrence of the pentylenetetrazole (PTZ)-induced seizures in mice was significantly prevented by CLZ, even when exposed a lower dose of CLZ-SLN after administration by the oral route. The behavioral severity and EEGs showing the PTZ-induced paroxystic activity in rats diminished significantly in the presence of CLZ alone (0.3 mg/kg), and were almost totally prevented in the rats treated with CLZ-SLN (equivalent to 0.3 mg/kg). The frequency, duration, and spreading of the spikes-wave of rats treated with CLZ-SLN decreased significantly as compared with CLZ alone, CLZ-MM, or the vehicle. These results show an in vitro-in vivo correlation in the enhanced blood-brain barrier permeability of SLN formulation, and a contribution of MM to the carrier effect of drugs toward the bloodstream and brain, where this pharmaceutical formulation of CLZ-SLN improves the anticonvulsant effect of this benzodiazepine, thus offering additional advantages after oral administration.
authors.affiliation: Laboratorio de Investigación y Posgrado en Tecnología Farmacéutica, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Estado de México, 54740, México; Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación, México, D.F., México; Section des Sciences Pharmaceutiques, Technologie Pharmaceutique, Université de Genève, Geneva, 41211, Switzerland.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Leyva-Gómez
authors.forename: María Eva
authors.initials: ME
authors.lastname: González-Trujano
authors.forename: Edith
authors.initials: E
authors.lastname: López-Ruiz
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Babette
authors.initials: B
authors.lastname: Wekslerg
authors.forename: Ignacio
authors.initials: I
authors.lastname: Romero
authors.forename: Florence
authors.initials: F
authors.lastname: Miller
authors.forename: Florence
authors.initials: F
authors.lastname: Delie
authors.forename: Eric
authors.initials: E
authors.lastname: Allémann
authors.forename: David
authors.initials: D
authors.lastname: Quintanar-Guerrero
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000627:therapeutic use; D002460:Cell Line; D002998:Clonazepam / Q000008:administration & dosage* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D004569:Electroencephalography; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010433:Pentylenetetrazole; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D004337:Drug Carriers; D008055:Lipids; D008823:Micelles; D002998:Clonazepam; D010433:Pentylenetetrazole
keywords: CNS; absorption enhancer; anticonvulsant; clonazepam; drug transport; electroencephalogram; lipids; micelles; pentylenetetrazole; solid lipid nanoparticles