¹Wyeth Research, Aster, PARIS La D|[eacute]|fense c|[eacute]|dex, France

Abstract

SRA-333 is a new potent and silent 5HT_1a antagonist which increased glutamatergic and cholinergic neurotransmission during cognitive processes. SRA-333 is proposed for the treatment of cognitive deficits associated with Alzheimer's disease. This was a randomized, double-blind, placebo-controlled, sequential, ascending single dose study in 24 healthy subjects to assess the safety, tolerability, PK and PD of SRA-333. Three dose levels (2, 5 and 10 mg) were assessed in cohorts of 8 subjects (6 active and 2 placebo). Assessments consisted of safety evaluation (vital signs, ECG, lab tests), up to 48 hours after dosing, determination of SRA-333 PK profile and cognitive assessment using the Cognitive Drug Research battery (Reading, UK) exploring attention, sensori-motor tasks and working and episodic memory. SRA-333 was well-tolerated up to a dose of 10 mg where dose limiting mild to moderate CNS adverse events occurred (light headedness, sensorial disturbances, dizziness). No individual clinically significant sustained individual drug-related changes were recorded in vital signs, ECGs and routine laboratory tests. No clinically relevant impairment in cognitive functions were observed. SRA-333 was rapidly absorbed (t_max |[sime]| 0.5h) and eliminated (half-life |[sime]| 6 to 8 hours). Plasma concentrations increased in a linear-proportional manner with increasing doses.

In summary, SRA-333 was safe and well-tolerated up to a dose of 10 mg. Its pharmacokinetic profile allowed a twice daily dosage regimen.