Tetrahydroaminoacridine–Lecithin Combination Treatment in Patients with Intermediate-Stage Alzheimer's Disease

Abstract

We studied the efficacy and safety of oral tetrahydroaminoacridine (THA) combined with lecithin in 52 patients with Alzheimer's disease. The maximal tolerated dose of THA (up to 100 mg per day) was determined during an eight-week titration period, after which the tolerated dose of THA or placebo was given during two sequential randomized periods of treatment lasting eight weeks each. Highly purified lecithin (4.7 g per day) was administered during all phases of the study. Efficacy was expressed in terms of scores on the Mini-Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rating Scale-II, and the behavioral scale of Reisberg et al. Safety was assessed by careful clinical monitoring as well as serial measurements of liver aminotransferases. Forty-six patients completed the titration period, and 39 completed the double-blind period, during which only the MMS score showed a small but significant increase (P less than 0.05) after four weeks of treatment with THA. Autonomic side effects of THA were common but mild. Reversible elevations of serum aspartate and alanine aminotransferase levels to three or more times the upper limit of normal occurred in 17 percent of patients; most of the patients affected were women. A liver biopsy performed in one patient showed resolving focal liver-cell necrosis. These studies fail to demonstrate a significant clinical benefit of THA given orally in a maximal dose of 100 mg per day over a period of eight weeks in combination with lecithin.

Blockade of nicotinic responses by physostigmine, tacrine and other cholinesterase inhibitors in rat striatum

“…However, other studies have shown little or no benefit with either drug (Ashford et al, 1981;Caltagirone et al, 1982;Sahakian et al, 1983;Chatellier & Lacomblez, 1990;Gauthier et al, 1990). In the light of recent evidence indicating that cognitive functioning can be enhanced by nicotinic receptor agonists and impaired by nicotinic blockers (Newhouse et al, 1988;Jones et al, 1992), it must be emphasized that the concentrations of physostigmine and tacrine shown to antagonize nicotinic responses in the present study, also inhibited AChE activity almost completely, and thus would not normally be achieved in the clinic.…”

Tacrine Treatment of Alzheimer’s Disease: Many Expectations,Few Certainties

“…Another 8 trials [11][12][13][14][15][16][17][18] with a total of 2,080 patients treated with THA (tables 2, 3) were in contrast with our inclusion criteria; nevertheless they are described in the discussion section to make our work more exhaustive. Studies using various doses and administration modalities of treatment, i.e.…”

THA – Historical Aspects, Review of Pharmacological Properties and Therapeutic Effects

“…No significant improvement in symptoms of AD was noted, and 15% of the patients developed hepatotoxicity from THA. Gau thier et al [36] did not find any significant clinical benefit of THA up to 100 mg and lecithin 4.7 g'day, over a period of 8 weeks, in a double-blind, crossover, multicenter study with 52 AD patients.…”