Invited Review Cholinesterase inhibitors for Alzheimer’s disease therapy: from tacrine to future applications

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Abstract

This review starts with an historical background of the pharmacological development of tacrine almost fifty years ago (1949). Tacrine is the first drug to be tested, clinically, on a large scale and to be registered (1993) for treatment of Alzheimer’s disease. For the first time, clinical results of four second generation cholinesterase inhibitors (ChEI) (donepezil, ENA 713, eptastigmine and metrifonate) are reviewed and compared with other ChEI such as tacrine, physostigmine and galanthamine. Data based on more than 6000 patients show that second generation drugs are well tolerated and show evidence of clinical efficacy. Differences are mainly due to frequency of side effects, number of drop outs and percentage of improved patients. These results also demonstrate the presence of clinical efficacy for all ChEI tested so far. Clinical mechanism of action, levels of efficacy and differences among various ChEI are discussed. Future potential indications are suggested. The present data indicate that optimization of effects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties.

Section snippets

A historical note

Cholinergic deficits in Alzheimer’s Disease (AD) have been well documented (cf. Giacobini, 1990). The reduction of cortical and CSF cholinergic markers are correlated with the extent of the neuropathology and with the severity of cognitive impairment. It is assumed that insufficient levels of acetylcholine (ACh) at cortical synapses will severely impair the neuromodulatory function of this neurotransmitter. We calculated that the difference in cortical ACh levels between normal elderly controls

Cholinesterase inhibitors: how do they work in ad? Is there a difference among compounds?

ChEIs presently in clinical trials in Japan, U.S.A. and Europe include less than a dozen compounds, most of which have already advanced to clinical phase III and three ChEIs (tacrine, ENA 713 and donepezil) are registered in U.S.A. and\or in Europe1(cf. Giacobini, 1996).It is likely in that the 2-year period (1997–1999) at least three ChEIs will be registered world-wide. The second generation of ChEIs, in order to replace tacrine, will have to fulfil specific requirements of efficacy and safety

Symptomatic effect of disease stabilization?

Analysing the available 6 months data shown in Table 1, it is possible to observe that patients treated with the active compound change little cognitively from baseline at the beginning treatment. As an example in a U.S.A. study with ENA 713, patients administered placebo for 26 weeks deteriorated over 4 points on the ADAS-cog compared to only 0.3 in patients given 6–12 mg\day of the drug (Anand et al., 1996). The same is true for metrifonate treatment. This suggests that the difference seen

Can the clinical efficacy of various ChEIs be compared?

ChEIs could differ from one another with respect to magnitude and duration of effect. In comparing present results of clinical trials and different drugs one should take into consideration the fact that these studies may differ from one another, depending on differences in selection criteria, age of subjects, severity of disease, concomitant illnesses and medications, variable instruments of assessment and side effect evaluation. In addition to these variables, in order to evaluate real

What makes the difference between various ChEIs?

The relation between percentage of peripheral ChE inhibition and cognitive (ADAS-cog) or global impression of change rated by the clinician (CGIC) effect is a relevant factor which is reported in Table 2. The data presented in Table 2 supports the pharmacological knowledge that brain ChE inhibition relates directly to an improvement of functional ACh levels. This relationship might vary quantitatively for each drug and each compound may produce various levels of cognitive improvement and

Is there a tolerance to the effects of AChEIs?

A combination of pharmacokinetic and pharmacodynamic effects of the drug such as down-regulation of muscarinic and nicotinic receptors and decreased ChE inhibition due to new enzyme synthesis, may be responsible for the tolerance to therapeutic effects seen in experimental animals and patients treated with ChEIs for 24 weeks or longer.

Last but not least, a problem of ChEI therapy is the early identification of those patients most likely to benefit from therapy. Correlation of therapy

The future of ad therapy with cholinesterase inhibitors

ChEIs are presently the drugs of choice for AD. In less than 10 years, starting from non-specific first generation drugs such as physostigmine, a second generation of more selective and better tolerated products has been developed. The data summarized here for the first time involved clinical trials of six different ChEIs using the same scales under relatively uniform conditions. Soon available data on these drugs originate from more than 6000 patients treated in 24–30 week phase III

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