Edward E Patterson1, Ilo E Leppik2,3, Lisa D Coles2, Michael Podell4, Charles H Vite5, William Bush6, James C Cloyd2. 1. Veterinary Medical Center, University of Minnesota, St. Paul, Minnesota, U.S.A. 2. Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, U.S.A. 3. UMP MINCEP Epilepsy Care, Minneapolis, Minnesota, U.S.A. 4. Chicago Veterinary Neurology and Neurosurgery, Chicago, Illinois, U.S.A. 5. School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. 6. Bush Veterinary Neurology Service, Leesburg, Virginia, U.S.A.
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.
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 humanepilepsy. 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.
Authors: I E Leppik; B A Boucher; B J Wilder; V S Murthy; C Watridge; N M Graves; R J Rangel; C A Rask; P Turlapaty Journal: Neurology Date: 1990-03 Impact factor: 9.910
Authors: Barbara G. Licht; Mark H. Licht; Kathleen M. Harper; Shili Lin; John J. Curtin; Linda L. Hyson; Kristen Willard Journal: Epilepsy Behav Date: 2002-10 Impact factor: 2.937
Authors: Lisa D Coles; Edward E Patterson; W Douglas Sheffield; Jaideep Mavoori; Jason Higgins; Bland Michael; Kent Leyde; James C Cloyd; Brian Litt; Charles Vite; Gregory A Worrell Journal: Epilepsy Res Date: 2013-08-18 Impact factor: 3.045
Authors: Irene Vuu; Lisa D Coles; Patricia Maglalang; Ilo E Leppik; Greg Worrell; Daniel Crepeau; Usha Mishra; James C Cloyd; Edward E Patterson Journal: Front Vet Sci Date: 2016-12-05