Harkoseride: Safety and Tolerability of a New Antiepileptic Drug (AED) in Patients with Refractory Partial Seizures.
Abstract number :
G.12
Submission category :
Year :
2000
Submission ID :
742
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Nathan B Fountain, Jacqueline A French, Michael D Privitera, Univ of Virginia, Charlottesville, VA; Univ of Pennsylvania, Philadelphia, PA; Univ of Cincinnati, Cincinnati, OH.
RATIONALE: Harkoseride (SPM 927) is a functionalized amino acid (ADD 234037) with affinity for the strychnine-insensitive glycine receptor on the NMDA receptor complex. Harkoseride has a good therapeutic index in epilepsy models and was well tolerated after I.V. and oral administration in healthy males. Human pharmacokinetic data indicated a plasma half-life of ? 12 hours; ? 1% protein binding and steady state was reached in 2-3 days after b.i.d. dosing. This study investigated the safety and tolerability of ascending doses of Harkoseride as adjunctive therapy in patients with refractory partial seizures. METHODS: Open-label multicenter study of patients with ? 2 partial seizures ( secondary generalization) per week and treated for ? 2 years. Current concomitant therapy limited to ? 2 AEDs. Compliance and seizure frequency were established during a 3 week baseline. Harkoseride could be titrated in 100 mg increments per week over 3 weeks to a maximum of 300 mg b.i.d. Patients were down-titrated over an additional week with a 2 week follow-up. RESULTS: Preliminary analyses revealed that 3 epilepsy centers enrolled 13 patients (9 males and 4 females) aged from 24-50 years (mean=34). During baseline all patients had complex partial seizures while 5 (38%) also had simple partial and 4 (31%) had secondary generalized seizures. The number of partial seizures ranged from 1-50 with an average of 9.9 at the last week of baseline. After the 1st, 2nd and 3rd week of Harkoseride therapy, the average seizure frequency was reduced from baseline to 8.5 (-14%), 6.5 (-34%) and 5.2 (-47%) respectively. After the dose reduction withdrawal phase, the seizure frequency increased to an average of 9.5. A single patient had 1 generalized seizure during Harkoseride therapy, while 5 had generalized seizures during withdrawal and follow-up. Three patients had serious adverse events that resulted in dose reduction. Eighty-four % (11/13) were titrated to the maximal daily dose of 600 mg. No adverse experience resulted in patients' discontinuation. CONCLUSIONS: Harkoseride is a new AED that merits further clinical study in a well-controlled setting. NINDS-SBIR