title: Canine status epilepticus treated with fosphenytoin: A proof of principle study.
abstract: OBJECTIVE
  There are a limited number of marketed intravenous antiepileptic drugs (AEDs) available to treat status epilepticus (SE). All were first developed for chronic therapy of epilepsy, not specifically for SE. Epilepsy and canine SE (CSE) occur naturally in dogs, with prevalence, presentation, and percentage of refractory cases similar to human epilepsy. The objective of this study was to determine if CSE treated with fosphenytoin (FOS) results in a similar responder rate as for people.
  
  
  METHODS
  A randomized clinical trial was performed for dogs with CSE. Dogs who presented during a seizure or who had additional seizures after enrolling received intravenous (i.v.) benzodiazepine (BZD) followed immediately by intravenous infusion of 15 mg/kg phenytoin equivalent (PE) of fosphenytoin (FOS) or saline placebo (PBO). If seizures continued, additional AEDs were administered per the standard of care for veterinary patients. Total and unbound plasma phenytoin (PHT) concentrations were measured.
  
  
  RESULTS
  Consent was obtained for 50 dogs with CSE. Thirty-one had additional motor seizures and were randomized to the study intervention (22 FOS and 9 PBO). There was a statistically significant difference in the 12 h responder rate, with 63% in the FOS group versus 22% in the placebo group (p = 0.043) having no further seizures. The unbound PHT concentrations at 30 and 60 min were within the therapeutic concentrations for people (1-2 μg/ml) with the exception of one dog. There was mild vomiting in 36% of the FOS group (7/22) within 20 min of FOS administration and none of the placebo group (0/9) (p = 0.064).
  
  
  CONCLUSIONS
  This proof of concept study provides the first evidence that FOS is tolerated and effective in canine SE at PHT concentrations clinically relevant for human SE. Furthermore, naturally occurring CSE can be utilized as a translational platform for future studies of novel SE compounds.
authors.affiliation: Veterinary Medical Center, University of Minnesota, St. Paul, Minnesota, U.S.A.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Patterson
authors.affiliation: Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, U.S.A.|UMP MINCEP Epilepsy Care, Minneapolis, Minnesota, U.S.A.
authors.forename: Ilo E
authors.initials: IE
authors.lastname: Leppik
authors.affiliation: Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, U.S.A.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Coles
authors.affiliation: Chicago Veterinary Neurology and Neurosurgery, Chicago, Illinois, U.S.A.
authors.forename: Michael
authors.initials: M
authors.lastname: Podell
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vite
authors.affiliation: Bush Veterinary Neurology Service, Leesburg, Virginia, U.S.A.
authors.forename: William
authors.initials: W
authors.lastname: Bush
authors.affiliation: Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, U.S.A.
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000008:administration & dosage; D004285:Dogs; D004311:Double-Blind Method; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D011446:Prospective Studies; D013226:Status Epilepticus / Q000097:blood / Q000188:drug therapy* / Q000662:veterinary*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D001569:Benzodiazepines; D010672:Phenytoin; C043114:fosphenytoin
keywords: Animal model; Dog; Emergency; Seizure; Translational