Table 2.

Summary of the studies on AChE–BuChE inhibition by rivastigmine

Authors	Study design	Animals	Main findings
Ogura et al47	In vitro	Male Wistar rats	Rivastigmine showed greater inhibitory potency (IC50) toward brain BuChE and AChE than donepezil under optimal assay conditions
Naik et al48	In vivo microdialysis	Adult male and female AChE−/− and AChE+/+ mice	Rivastigmine unlike donepezil increased hippocampal acetylcholine levels in AChE knockout mice (AChE−/−), suggesting that rivastigmine enhances extracellular acetylcholine levels by inhibiting BuChE
Cerbai et al49	In vivo microdialysis and HPLC	Male Wistar rats	BuChE in addition to AChE co-regulates acetylcholine activity in rat cerebral cortex
Furukawa-Hibi et al50	In vivo	Male, 5-week-old ICR mice and control mice	Inhibiting BuChE is a therapeutic strategy for ameliorating cognitive dysfunction in AD, and dual AChE/BuChE inhibition maximizes therapeutic efficacy

Authors	Study design	Indication	Number of patients	Main findings
Clinical studies
Potkin et al51	26 weeks, DB, PC study and FDG-PET	Mild-to-moderate probable AD	n=27 Rivastigmine 3 mg/day: 5; rivastigmine 6 mg/day: 7; rivastigmine 9 mg/day: 8; placebo: 7	Metabolism increased in brain hippocampus and prefrontal cortex in rivastigmine responders
Rombouts et al52	fMRI study	Mild AD	n=7 Rivastigmine 3 mg single dose	Rivastigmine increased bilateral activation in the fusiform gyrus and prefrontal cortex
Kaasinen et al53	[11C]MP4A PET study	Probable AD	n=11 Donepezil 10 mg/day: 6; rivastigmine 9 mg/day: 5	Rivastigmine 9 mg/day induced AChE inhibition in frontal, temporal, and parietal cortices, with greater AChE inhibition in the frontal cortex than the temporal cortex
Kennedy et al34	Single-dose study	Healthy volunteer	n=8 Rivastigmine 3 mg, placebo	Decrease in the CSF AChE and BuChE activity was observed following a 3 mg single oral rivastigmine dose
Cutler et al54	OL, multiple-dose study	Probable AD	n=18 Rivastigmine 1, 2, 3, 4, 5, or 6 mg bid (three patients per group)	Rivastigmine 6 mg bid oral dose showed a maximum mean inhibition
Giacobini et al28	OL study	Probable AD	n=18 Rivastigmine 1, 2, 3, 4, 5, or 6 mg bid (three patients per group)	Cognitive improvement with rivastigmine in AD is associated with BuChE inhibition in addition to inhibiting AChE in the CSF
Darreh-Shori et al27	12-month, OL study	Mild AD	n=11 Rivastigmine dose increments of 1.5 mg bid every 2 weeks	Rivastigmine inhibits both AChE and BuChE and the sustained cholinesterase inhibition correlates with cognitive abilities of patients with AD after treatment
Eskander et al55	Ex vivo study	AD	Eight brains from AD patients	Rivastigmine also inhibits cholinesterases (AChE and BuChE) bound to cortical plaques and tangles in AD in dose-dependent manner
Nordberg et al56	13-week, randomized, OL comparative study	Mild-to-moderate AD	n=63 Rivastigmine: 22, donepezil: 20, galantamine: 21	Rivastigmine reduces both AChE and BuChE activities, but donepezil and galantamine do not inhibit BuChE activity
Parnetti et al57	Patients enrolled in clinical trials with AChE inhibitors were recruited from three European centers	Probable AD	n=144 Donepezil 5 or 10 mg⁄day: 104; galantamine 12 or 16 mg⁄day: 15; rivastigmine 6, 9, or 12 mg⁄day: 16; placebo: 9	Rivastigmine decreased CSF AChE and BuChE activity, whereas donepezil or galantamine treatment increased CSF AChE activity but did not influence CSF BuChE activity

Abbreviations: AChE, acetylcholinesterase; AD, Alzheimer’s disease; bid, twice daily; BuChE, butyrylcholinesterase; CSF, cerebrospinal fluid; DB, double-blind; FDG-PET, ¹⁸F-fluorodeoxyglucose-positron emission tomography; fMRI, functional magnetic resonance imaging; HPLC, high-performance liquid chromatography; IC₅₀, half maximal inhibitory concentration; ICR, imprinting control region; OL, open-label; PC, placebo-controlled; [¹¹C]MP4A PET, N-[¹¹C]methylpiperidyl-4-acetate-positron emission tomography.