Canine status epilepticus treated with fosphenytoin: A proof of principle study

Ned Patterson, Ilo E Leppik, Lisa D Coles, Michael Podell, Charles H. Vite, William Bush, James C Cloyd

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Objectives 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). Significance 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.

Original languageEnglish (US)
Pages (from-to)882-887
Number of pages6
JournalEpilepsia
Volume56
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Status Epilepticus
Canidae
Phenytoin
Seizures
Dogs
Placebos
Epilepsy
Anticonvulsants
Standard of Care
fosphenytoin
Benzodiazepines
Intravenous Infusions
Vomiting
Randomized Controlled Trials
Therapeutics

Keywords

  • Animal model
  • Dog
  • Emergency
  • Seizure
  • Translational

Cite this

Canine status epilepticus treated with fosphenytoin : A proof of principle study. / Patterson, Ned; Leppik, Ilo E; Coles, Lisa D; Podell, Michael; Vite, Charles H.; Bush, William; Cloyd, James C.

In: Epilepsia, Vol. 56, No. 6, 01.06.2015, p. 882-887.

Research output: Contribution to journalArticle

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abstract = "Objectives 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). Significance 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.",
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