Pharmacological Basis of Cholinergic Therapy in Alzheimer Disease

Abstract

Cholinesterase inhibitors (ChEI) presently in clinical trials or in current use (1998) in Japan, USA and Europe include less than ten drugs. Most of these compounds have advanced to clinical phase III and IV and two (tacrine and donepezil) are registered in USA and in Europe (1). Other two compounds (rivastigmine and metrifonate) are close to registration. This second generation ChEI, in order to replace tacrine, had to fulfill specific requirements such as lower toxicity (1). Based on current selection criteria and occurrence of complications a number of ChEI has been discontinued. Are there major differences among various compounds with regard to efficacy, percentage of treatable patients and incidence of side effects? Table 1 compares the effect of six ChEI on ADAS-cog test using ITT (intention to treat) criteria. The duration of clinical trials varied from 24 to 30 weeks and the number of treated patients was above 4000. All six ChEI produced statistically significant improvements evaluated with scales of standardized and internationally validated measures of both cognitive and non-cognitive function. The magnitude of cognitive effects measured with the ADAS-cog scale is similar for all six drugs either expressed as difference between drug- and placebo-treated patients or by the difference of drug-treated patients from baseline (Table 1) (2–7). This similarity in cognitive improvement suggests a ceiling effect of approximately five ADAS-cog points average for ChEI tested in mild to moderate (CDR 1–1.5) stages of the disease and at present level of dosage. This result does not imply that maximal effect had been reached with a each drug. The high percentage of drop-outs and more severe side-effects seen with some drugs such as tacrine (hepatotoxicity and general cholinergic toxicity), suggests a limit in practically achievable levels of ChE inhibition as well as in drug effect. Similarity of clinical efficacy is emphasized by the practical identical effect on global scales such as the clinicians interview-based impresssion of change-plus (CIBIC-plus) of 0,4 points difference seen for tacrine, rivastigmine and metrifonate. These drugs have very different chemical structures and pharmacological profiles.