Results of 4 double-blind, placebo-controlled clinical trials of donepezil, involving more than 1,900 individuals with mild to moderate AD, have been published recently. In all, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 mg/d and 10 mg/d), relative to placebo. Similar benefits were reported for global functioning.
The long-term clinical efficacy and safety of donepezil versus placebo across 1 year in patients with mild to moderate AD was investigated.14 The Gottfries-Brane-Steen global assessment for rating dementia symptoms demonstrated the benefit of donepezil over placebo at weeks 24, 36, and 52, and at the study end point. Advantages of donepezil were also observed in cognition and ADL.
Donepezil also appears to work for patients with moderate to severe AD. In a recent 24-week study,15 patients receiving donepezil showed benefits on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+), compared with placebo, at all visits up to week 24 and at the study’s end point. All other secondary measures showed significant differences between the groups in favor of donepezil at the end of the study. These data suggest that donepezil’s benefits extend into more advanced stages of AD than those previously investigated, with good tolerability.
Clinical trials of rivastigmine (1.5-6 mg twice daily PO) have also demonstrated benefits on cognitive and global measures.16 The efficacy of rivastigmine tartrate (ENA 713) in patients with mild to moderately severe Alzheimer’s disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with rivastigmine 6 to 12 mg/d had significantly better cognitive function than did patients originally treated with placebo.17- 19
BASIC PROPERTIES OFTHEAChE INHIBITORS
Donepezil is a second-generation, piperidine-class, selective and reversible acetylcholinesterase (AChE) inhibitor. It is structurally dissimilar from other established AChE inhibitors.
Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70h, lending itself to once-daily administration.11
Rivastigmine (ENA 713, or carbamoylatine) is an AChE inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system compartment than it does in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Rivastigmine also preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer’s disease (AD).
Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug.
Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine.12
Galantamine is an allosterically potentiating ligand that modulates nicotinic cholinergic receptors (nAChR) to increase acetylcholine release as well as acting as an AChE inhibitor. In preclinical experiments, the drug significantly improves learning, reduces AChE levels, and increases nicotinic receptor binding. Action of galantamine is on the most abundant nAChR in the human brain, the alpha4/beta2subtype.13
Clinical trials of galantamine (4-12 mg/bid PO) have demonstrated similar benefits.20 Following a 4-week placebo run-in, patients were randomized to 1 of 4 treatment arms: placebo or galantamine escalated to final maintenance dosages of 8, 16, or 24 mg/d for a 5-month treatment phase. At study’s end, the galantamine-place-bo differences on the cognitive subscale of the AD Assessment Scale were 3.3 points for the 16 mg/d group and 3.6 points for the 24 mg/d group. Treatment discontinuations due to adverse events were low in all galantamine groups (6% to 10%) and comparable with that in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild.
Other studies examining galantamine have demonstrated similar clinical benefits.8, 21
When using AChE inhibitors, the slope of cognitive decline is similar in treated and untreated patients after the initial improvement. These drugs essentially do not reverse the disorder’s course but shift upward the curve describing the time course of cognitive decline. This applies also to behavioral and functional benefits. Thus the benefit obtained is symptomatic and not neuroprotective, and is lost after discontinuing the medications.