A BRIDGING (SAFETY TOLERANCE) STUDY OF BESIPIRDINE HYDROCHLORIDE IN PATIENTS WITH ALZHEIMERS-DISEASE

Besipirdine hydrochloride is a novel compound with cholinergic and adr energic activity being investigated as a treatment for Alzheimer's dis ease (AD). The pharmacodynamics of some anti-dementia drugs are known to differ in patients with AD as compared with elderly normals. The pr esent study was designed to determine the maximum tolerated dose (MTD) of multiple oral doses of besipirdine in AD patients. Twelve AD patie nts (NINCDS/ADRDA criteria; 7M, 5F, ages 58-75, mean age 65) were rand omized to besipirdine (n=9) or placebo (n=3) in a double-blind, parall el-group, rising-dose design. Doses were 10, 20, 30, and 40 mg bid for 2 days each, followed by 50 and 60 mg bid for 5 days each. The most c ommon adverse events were asymptomatic postural hypotension and asympt omatic bradycardia. Two patients on active drug developed severe adver se events: 1 after 3 days at 50 mg bid (nausea and vomiting); 1 after 3 days at 60 mg bid(angina). Due to the anginal episode, the study was terminated on Day 17. Plasma concentrations increased linearly with d ose for besipirdine and its major metabolite. The two patients who dev eloped severe adverse events had the highest plasma concentrations mea sured. Besipirdine 50 mg bid was considered the maximum tolerated dose (MTD).