Donepezil has the longest plasma half-life at about 70 hours compared with 6 hours for galantamine, 3 hours for tacrine, and 1.5 hours for rivastigmine (this has the practical advantage that it is excreted quickly from the body and so relief from side effects is much more speedy than with the longer-acting compounds). The half-life also
has implications for the daily dosing regimen: the advantage of donepezil is that it only needs to be given once a day. Tacrine This was the first drug to be introduced and, in many ways, was the gold standard by which the others were measured. The drug has EGFR inhibitor positive Inhibitors,research,lifescience,medical effects on cognitive function at dosages of 160 mg/day, and benefits have been seen in terms of ADL and global function.18,19 Unfortunately, almost half of all patients experience liver side effects, usually a rise in transaminases, and so a search began for an agent as effective as tacrine, but without side effects. Donepezil As a piperidinc-based compound, the introduction of donepezil was important because of its lack of liver Inhibitors,research,lifescience,medical side effects and the convenience of once-daily dosing. One multinational study20 involved patients Inhibitors,research,lifescience,medical in Australia, Belgium, Canada, France, Germany, Ireland,
New Zealand, South Africa, and the UK. Fight hundred and eighteen (818) patients were randomized to receive placebo (n=274), 5 mg/day donepezil (n=271), or 10 mg/day donepezil (n=273).The mean age of patients was just over 70 and they all satisfied the NINCDS/ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer
Disease and Related Disorders Association)21 criteria for probable Alzheimer’s disease. Inhibitors,research,lifescience,medical Patients with mild-to-moderate impairment were included, as assessed by an MMSE score of between 10 and 26 and a CDR of 1 (mild) or 2 (moderate). The study lasted 30 weeks: 24 weeks with a double-blind, placebo-controlled phase followed by a single-blind placebo washout Inhibitors,research,lifescience,medical over 6 weeks. Patients started with 5 mg/day donepezil for 7 days followed by 10 mg/day. The positive effects on the ADAS-Cog arc shown in Figure 1. The percentage of patients rated as improved was 21 % for 5 mg/day, 25% for 10 mg/day, and 14% for placebo. The pattern of side effects (mostly related to the digestive system, the eg, diarrhea, nausea, and vomiting, understandable in terms of the physiological effect of a cholinergic drug) was the same (10%) for placebo and 5 mg/day of the drug, and double that in those taking the higher dose. The IDDD was used to assess ADL and the drug showed a protective effect against the decline and activity that occurred with placebo. A similar USA-based study22 was in accordance with these findings and there was evidence that the 10 mg/day dosage was superior to the 5 mg/day dosage. Figure 1. Effect of donepezil, 5 and 10 mg/day, and placebo on Alzheimer’s Disease Assessment Schedule-Cognitive Section (ADAS-Cog) scores. Data are least square means±SE. *P<0.0001 ; **P=0.