This application proposes a study that, if successful, will lead directly to subsequent projects that will facilitate the translation of new drugs discovered from laboratory models of status epilepticus to treatment of human status epilepticus (HSE). The goals of this study are to: 1) determine if naturally occurring status epilepticus in dogs is a valid platform to test compounds found effective in experimental models of SE for efficacy, safety and tolerability;and 2) initiate a process of therapeutic development to make drugs discovered in the laboratory available for the treatment of HSE. Results will provide information essential for INDs and IRB applications for human clinical SE trials. Demonstration that fosphenytoin (FOS), a prodrug of phenytoin (PHT), is statistically superior to placebo and has a response rate similar to that in humans will establish the canine SE platform as a valid, inexpensive, and rapid means to translate agents discovered from laboratory SE models into studies of HSE. Convulsive HSE affects an estimated 152,000 persons and causes 42,000 deaths each year in the USA (1). Current guidelines for treatment incorporate drugs developed 30 to 70 or more years ago (phenytoin, benzodiazepines), which are not successful in more than 1/3 to 1/2 of cases (4). Loading doses of PHT are included in the current international guidelines for the treatment of HSE (3). FOS was developed to avoid the toxic effects IV PHT. FOS is now widely prescribed for HSE and will be used in this study (17). Canine status epilepticus (CSE) is commonly encountered in clinical veterinary practice. The causes and presentation are similar to those seen in HSE (10,11). We propose to treat dogs with established CSE with loading doses of FOS designed to attain PHT concentrations similar to those attained in humans following loading doses of 18 mg/kg. Our study will be a randomized, double-blind, placebo-controlled investigation of FOS vs. saline in dogs with established CSE. It will include a robust rescue protocol. Using a placebo control greatly increases the power and decreases the number of subjects needed. Validation of the platform will be based on: 1) statistical superiority of the FOS (50% response) vs. placebo (10% response), powering the study for a 40% difference;and 2) a response rate of approximately 50% for FOS, similar to that observed for PHT in HSE trials. If we are able to demonstrate the validity of CSE as a platform for testing drugs discovered in animal models, a process of therapeutic development can be initiated that will enable: 1) establishment of a national network of veterinary emergency care departments similar to the human Neurological Emergencies Treatment Trials (NETT) system;2) use the CNETT to test specific novel agents 3) make the CNETT available to basic scientists and industry to test new compounds for HSE;and results from 2 and 3 may be used to inform IND applications for treatment of HSE.

Public Health Relevance

This application proposes a proof of principle study that can lead to subsequent projects that will facilitate the translation of new drugs discovered from laboratory models of status epilepticus to treatment of human status epilepticus . The jump from small animal discovery of new drugs to human testing is very great and has greatly limited progress. We propose to study a commonly used drug for human status epilepticus, fosphenytoin, in dogs with naturally occurring status epilepticus, to show that dogs respond similarly to humans and that testing new drugs in dogs will develop information useful for obtaining permission to test these in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS072166-02
Application #
8144793
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2010-09-17
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$184,975
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Vuu, Irene; Coles, Lisa D; Maglalang, Patricia et al. (2016) Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy. Front Vet Sci 3:107
Patterson, Edward E; Leppik, Ilo E; Coles, Lisa D et al. (2015) Canine status epilepticus treated with fosphenytoin: A proof of principle study. Epilepsia 56:882-7
Coles, Lisa D; Leppik, Ilo E; Patterson, Edward E et al. (2015) Use of IV fosphenytoin pharmacokinetics to determine the loading dose for a clinical trial of canine status epilepticus. Epilepsia 56:888-94
Leppik, Ilo E; Patterson, Edward N; Coles, Lisa D et al. (2011) Canine status epilepticus: a translational platform for human therapeutic trials. Epilepsia 52 Suppl 8:31-4