Tacrine

Abstract

Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer's disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer's disease--a welcome advance in an area previously devoid of acceptable treatment options.

Enduring effects of tacrine on cocaine-reinforced behavior: Analysis by conditioned-place preference, temporal separation from drug reward, and reinstatement

“…Besides cholinesterase inhibition, tacrine has effects on neurotransmitters other than acetylcholine (Wagstaff and McTavish, 1994). Tacrine can inhibit MAO-A and to a lesser extent MAO-B (Adem et al, 1989).…”

Nantenine as an acetylcholinesterase inhibitor: SAR, enzyme kinetics and molecular modeling investigations

“…Four compounds are commonly prescribed for treatment of AD based on this mechanism of action namely galanthamine ( 1 ), tacrine ( 2 ), donepezil ( 3 ) and rivastigmine ( 4 ) (Figure 1) [13,14]. These therapeutics offer short-term improvement in treating symptoms of the disease with modest benefits in slowing the decline in behavior, function and cognition associated with the disease [15-17]. All of the approved AChE inhibitors have potentially serious side-effects especially with long-term use, and more efficacious and safer alternatives are desirable [18-21].…”

Neuroactive Multifunctional Tacrine Congeners with Cholinesterase, Anti-Amyloid Aggregation and Neuroprotective Properties

“…There is also a high incidence of side effects in the use of tacrine–autonomic symptoms such as gastrointestinal disturbance and hypotension. Additionally, the therapeutic index of tacrine is so small that it is both critical and difficult to find the optimum dose, as individual patients vary greatly in their responsiveness to the treatment [10-12]. …”