Canine status epilepticus: A translational platform for human therapeutic trials

Convulsive HSE affects an estimated 152,000 persons and causes 42,000 deaths each year in the USA (DeLorenzo, 2006). Treatment of human status epilepticus (HSE) is based on studies performed more than two decades ago using drugs developed 10 to 50 years or more before the studies. Successful treatment rates were only 67% with lorazepam and 44% with phenytoin (Treiman DM et al., 1998). These drugs now form the basis of the international HSE treatment guidelines (Kalviainen, 2007). A major barrier to the development of new drugs for HSE is providing enough pre-clinical evidence of safety and efficacy to justify the of conduct human studies. Results from studies performed in small animals with experimental SE may not be sufficient to convince trial sponsors to proceed with development of drugs in humans. Further, the available drugs for HSE were initially developed for chronic treatment of epilepsy, and only used for HSE after intravenous preparations became available. The mechanisms driving HSE may differ from the triggers of isolated seizures, and the best drugs for chronic epilepsy may not be the best choices to abort HSE. During the 2007 London Colloquium on SE, it became clear that many agents tested in small animal SE models had the potentially significant advantages over current agents. One of many of these is NS 1209, which is very effective in a model of status epilepticus but is not being developed for human use (Pitkanen A et al., 2007). However, many of these are not candidates for chronic epilepsy therapy, thus they will not proceed to clinical development. This led us to consider using CSE as a translational platform. The small animal (rodent) SE models have two shortcomings, which make it difficult to apply results to treating HSE. First, none of the models have counterparts in the human condition; they are usually induced by chemicals or electrical kindling (Sloviter RS et al., 2007). Secondly, scaling doses from rodents to humans involves a body size difference of more than 4000 fold and scaling is not linear (Leppik IE, 1998). This enormous difference may lead to substantial errors in selecting doses for humans. Clearly a test species having naturally occurring SE similar to humans and closer in terms of pharmacokinetic characteristics would be very useful.