Cyclooxygenase-2 Inhibition as an Add-On Strategy in Drug Resistant Epilepsy-A Canine Translational Study

Abstract

Drug-resistant epilepsy is a common complaint in dogs and affects up to 30% of dogs with idiopathic epilepsy. Experimental data suggest that targeting cyclooxygenase-2 (COX-2) mediated signaling might limit excessive excitability and prevent ictogenesis. Moreover, the role of COX-2 signaling in the seizure-associated induction of P-glycoprotein has been described. Thus, targeting this pathway may improve seizure control based on disease-modifying effects as well as enhancement of brain access and efficacy of the co-administered antiseizure medication. The present open-label non-controlled pilot study investigated the efficacy and tolerability of a COX-2 inhibitor (firocoxib) add-on therapy in a translational natural occurring chronic epilepsy animal model (client-owned dogs with phenobarbital-resistant idiopathic epilepsy). The study cohort was characterized by frequent tonic-clonic seizures and cluster seizures despite adequate phenobarbital treatment. Enrolled dogs (n = 17) received a firocoxib add-on therapy for 6 months. Tonic-clonic seizure and cluster seizure frequencies were analyzed at baseline (6 months) months during the study (6 months). The responders were defined by a substantial reduction of tonic-clonic seizure and cluster seizure frequency (≥50%). In total, eleven dogs completed the study and were considered for the statistical analysis. Two dogs (18%, 2/11) were classified as responders based on their change in seizure frequency. Interestingly, those two dogs had the highest baseline seizure frequency. The overall tolerability was good. However, given the low percentage of responders, the present data do not support an overall considerable efficacy of COX-2 inhibitor add-on therapy to overcome naturally occurring phenobarbital-resistant epilepsy in dogs. Further translational evaluation should only be considered in the canine patients with a very high baseline seizure density.

Keywords: P-glycoprotein; blood brain barrier; coxib; dog; idiopathic epilepsy; pharmacoresistance; seizures; treatment study.

Figure 1

Schematic illustration of the study design. The study course consisted of a continuous treatment period for the first 56 days, followed by a 14-day alternating treatment period for 112 days (total study period 168 days). The alternating treatment protocol was selected to lower the risk of potential firocoxib adverse events. Antiseizure medication was not changed during the firocoxib add-on phase, use of diazepam rectal tubes for emergency management of seizures was allowed. Clinical examinations and blood tests were performed on a regular base throughout the entire study period. Study participation was denied to any dog with pre-existing signs of gastrointestinal disease, renal disease or pre-treatment with any non-steroidal anti-inflammatory drug or glucocorticoids.

Figure 2

Pairwise comparisons of the monthly seizure and cluster seizure frequency of the study population (n = 11) before and during firocoxib add-on treatment. (A) Seizure frequency: The median seizure frequency for the study population at baseline and during firocoxib add-on treatment was 3.5 (range 2–11) and 4.0 (range 2–8), respectively. The median seizure frequency did not significantly differ between the baseline period and the firocoxib add-on treatment phase (p =0.59). Seizure frequency decreased considerably (≥50%) in two dogs with the highest seizure frequency. (B) Cluster seizure frequency: The median cluster seizure frequency at baseline and during firocoxib add-on treatment was 0.8 (range 0–2) and 1.0 (range 0–2), respectively. The cluster seizure frequency did not significantly differ between the baseline period and the firocoxib add-on treatment phase (p = 0.57).

Figure 3

Bar graph showing the individual monthly seizure frequency at baseline and during firocoxib add-on treatment. Six dogs showed a decrease in seizure frequency and five dogs showed an increase in seizure frequency. Only two dogs (cases 008,017) were classified as responders (R) defined by a seizure frequency reduction of ≥50%. None of the dogs became seizure-free.