Clinical experiences and biochemical findings with tacrine (THA).

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 occurred 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.

A comparison of propofol and methohexital as anesthetic agents for ECT: effects on seizure duration, therapeutic outcome, and memory.

The effects of the anesthetic agents propofol and methohexital on seizure duration, clinical outcome, recovery, and memory in electroconvulsive therapy (ECT) were studied in a double-blind trial. The study comprised 53 patients, 47 patients with major depression and six patients with other diagnoses according to DSM-III. Several recent clinical studies with a crossover design have shown a reduced seizure duration for anesthesia with propofol in comparison with both methohexital and thiopental. Propofol significantly reduced the seizure duration in this study without reducing the therapeutic outcome as measured by the Montgomery-Asberg Depression Rating Scale. Propofol did not significantly alter the length of the course of ECT; however, a slightly prolonged course for women cannot be completely ruled out. There were no significant differences between the two agents in effects on recovery times after anesthesia and on anterograde memory. In general, it seems that propofol is as effective as methohexital as an induction agent for ECT.

Tacrine in Alzheimer's disease: pharmacokinetic and clinical comparison of oral and rectal administration.

In a previous pharmacokinetic study in Alzheimer patients great inter-individual variation and low oral bioavailability of the cholinesterase inhibitor tacrine (tetrahydroaminoacridine, THA) were found. In the present investigation oral and rectal administration of tacrine were compared with the aim to find a route for improved bioavailability through diminished first-pass metabolism in the liver. Eight patients suffering from Alzheimer's dementia were given tacrine by oral (25 and 50 mg b.i.d.) and rectal (12.5 and 25 mg b.i.d.) routes for 1 week with 4-6 weeks washout in between. Drug hydroxylation capacity in the patients was determined using the debrisoquine test. Levels of tacrine in plasma and cerebrospinal fluid (CSF) were determined and the cognitive performance was examined by the Mini-Mental State Examination (MMSE) and the Alzheimer Deficit Assessment Scale (ADAS). Tacrine was well tolerated in all but one patient, a slow hydroxylator, who developed an aplastic anemia. MMSE and ADAS scores did not significantly change, except for word recall which was improved on tacrine when given by the rectal route. Pharmacokinetic analysis of the two administration routes revealed that the drug dose may be reduced by almost 50% when given rectally compared to orally. Concentrations of tacrine in the CSF were significantly lower and correlated linearly with the concentrations in plasma.

Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer patients.

The pharmacokinetics of tetrahydroaminoacridine (THA) was studied in patients suffering from Alzheimer's dementia. Single doses of the drug were administered by intravenous (15 mg), oral (50 mg) and rectal routes (25 mg). Pharmacokinetic parameters were related to clinical and biochemical effects in patients who, in a separate study, participated in a clinical trial of oral THA. The bioavailability of THA was low and varied considerably between subjects. Clinical improvement and occurrence of elevated liver enzymes correlated positively with drug bioavailability. Acetyl and butyryl cholinesterase activities in the plasma did not change following THA administration. Rectally administered THA had a higher bioavailability than orally administered THA in three subjects who were given the drug by both routes. These results indicate that a clinical trial of rectal THA would be justified as this administration route may improve resorption and diminish first-pass metabolism of the drug in the liver compared with oral administration.

One year on tacrine (THA): clinical and biochemical effects in patients with dementia of the Alzheimer type.

Fourteen patients suffering from dementia of the Alzheimer type were treated with tacrine (tetrahydroaminoacridine, 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.