A PILOT-STUDY OF ORAL PHYSOSTIGMINE PLUS YOHIMBINE IN PATIENTS WITH ALZHEIMER-DISEASE

Effective symptomatic treatment of Alzheimer's disease (AD) may requir e a combination of agents that augment cholinergic as well.as noradren ergic neurotransmission. We conducted a pilot study of physostigmine p lus oral yohimbine challenge in AD. Ten patients were enrolled in a 12 -day double-blind protocol. Each patient received placebo q2h while aw ake for 5 days, followed by physostigmine 2 mg q2h while awake for 7 d ays. During each of these drug conditions, yohimbine challenges were a dministered at oral doses of 10 and 20 mg in a placebo-controlled mann er. There was no significant improvement in Alzheimer's Disease Assess ment Scale test performance for six patients for whom complete cogniti ve data were obtained for the 6 challenge days. Nine patients tolerate d the protocol with no clinically significant changes in blood pressur e, pulse, or electrocardiogram (ECG), and no cardiovascular, gastroint estinal, or autonomic toxicity. One patient complained of chest discom fort associated with tachycardia, a modest rise in blood pressure, and had t-wave inversion in a single precordial lead. These signs and sym ptoms resolved within a few hours. Serial ECG tracings and cardiac enz ymes revealed no evidence of myocardial injury. This pilot study did n ot reveal major cognitive improvement with this regimen, but underscor es the importance of careful cardiovascular monitoring during future c ombined cholinergic-noradrenergic therapies in AD.