title: A new derivative of valproic acid amide possesses a broad-spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage.
abstract: OBJECTIVE
  sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death.
  
  
  METHODS
  The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6-Hz psychomotor; subcutaneous (s.c.) metrazol-, s.c. picrotoxin, s.c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine-resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N-methyl-D-aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE-induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD-treated rats that were protected against pilocarpine-induced convulsive SE was examined 10-14 days post-SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman-induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model.
  
  
  RESULTS
  SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD(50)/ED(50)]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED(50) for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpine-induced SE. When administered 20 and 40 min after SE onset, SPD (100-174 mg/kg) produced long-lasting efficacy (e.g., 4-8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED(50) values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK-PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman-induced seizures) and 12-50 mg/L (40 min after the onset of soman-induced seizures). The time to peak (t(max)) pharmacodynamic effect (PD-t(max)) occurred after the PK-t(max), suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD.
  
  
  CONCLUSIONS
  The results demonstrate that SPD is a broad-spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement.
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Anitha B
authors.initials: AB
authors.lastname: Alex
authors.forename: Amanda
authors.initials: A
authors.lastname: Pollock
authors.forename: Naama
authors.initials: N
authors.lastname: Hen
authors.forename: Tawfeeq
authors.initials: T
authors.lastname: Shekh-Ahmad
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Dan
authors.initials: D
authors.lastname: Kaufmann
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy*; D013226:Status Epilepticus / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000577:Amides; D000927:Anticonvulsants; D018696:Neuroprotective Agents; C570212:sec-butyl-propylacetamide; C045179:valnoctamide; D014635:Valproic Acid