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The cognitive decline in Alzheimer's disease has been shown to correlate with deficits in central cholinergic neurotransmission. Among various treatment attempts using cholinergic drugs a trial of the cholinesterase inhibitor tetrahydroaminoacridine (THA) (Summers et al., 1986) attracted considerable interest due to the positive effects reported on dementia symptoms. We have studied the effects of THA and placebo in a double-blind crossover trial over 9 weeks in 15 patients with dementia of Alzheimer type. Doses of the drug (75-150mdday) were titrated for each patient before entering the study. Clinical and biochemical effects were monitored using a battery of psychological tests, clinical rating scales and laboratory tests, including measurements of monoamine metabolites in the cerebrospinal fluid (CSF). The clinical results were mostly negative. Almost half of the patients had elevated liver enzymes (ALT and AST) in the THA period and these subjects showed more improvements of clinical ratings and psychological tests than did the patients without elevated liver enzymes. Levels of acetylcholine and the monoamine metabolites HVA and 5-HIAA in CSF were elevated on THA. The results indicate that THA has a therapeutic potential, although its pharmacokinetic profile and its liability to induce liver damage may limit the clinical use of the drug in the future.

Fourteen patients suffering from dementia of the Alzheimer type were treated with tacrine (tetrahydrominoacridine, THA) for 1 year in an open trial. Clinical results were evaluated every third month with neuropsychological tests and rating scales. During the dose-finding, two patients were temporarily withdrawn from medication and one patient was excluded because of elevated levels of liver enzymes. With individualized doses the treatment caused few side effects. Plasma levels of THA varied substantially among patients and correlated with elevation of liver enzymes but not with clinical response. Two patients showed a gradual increase in plasma levels of THA despite unchanged doses. Although results of the neuropsychological tests and clinical ratings were mostly negative, the study indicates that THA can be administered safely for prolonged periods of time. Clinical observations and dose-titration strategy in relation to side effects are discussed.

A clinical comparison of tacrine (THA) and placebo was performed in 15 Alzheimer patients using a double blind crossover technique over 4 plus 4 weeks with one drug‐free week in between. Treatment results, as evaluated by clinical rating scales and neuropsychological tests, were mostly negative. Side effects were few, except for elevation liver enzymes which occured in one third of the patients. CSF levels of the monoamine metabolites HVA and 5‐HIAA increased on tacrine as evidence for activation of dopamine and serotonin pathways through cholinergic receptors. Pharmacokinetic investigations showed that the oral bioavailability of tacrine was low and greatly varying between subjects. Patients with high bioavailability of the drug tended to improve more, and also to have more liver enzyme elevations, than those with low bioavailability. A gel preparation for rectal administration was manufactured for comparison of plasma levels attained during one week's treatment with levels attained with oral capsules. Preliminary results indicate that the dose of tacrine can be reduced to 50 per cent when administered rectally, probably as by this route the rapid first‐pass metabolism of the drug in the liver is diminished. A clinical trial of tacrine via the rectal route would be justified as this could decrease the number of patients with liver side effects and increase the number of patients improving on the treatment.

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