Cilostazol Add-On Therapy in Patients with Mild Dementia Receiving Donepezil: A Retrospective Study

Abstract

GoalCombinatorial therapy directed at both vascular and neurodegenerative aspects of dementia may offer a promising strategy for treatment of dementia, which often has a multifactorial basis in the elderly. We investigated whether the phosphodiesterase III inhibitor cilostazol, which is often used in the prevention of stroke and peripheral artery disease, may delay cognitive decline in the elderly receiving donepezil.MethodsMedical records were retrospectively surveyed to identify patients who had received donepezil for more than one year and had undergone Mini-Mental State Examination (MMSE) at least at two time points. Those with an initial MMSE score of less than 27 points were subjected to analysis (n = 156), with a cut-point of 21/22 applied to assign them to mild (n = 70) and moderate/severe (n = 86) dementia. The change of total MMSE score per year was compared between patients who had received donepezil and those given both donepezil and cilostazol.FindingsIn patients with mild dementia who had received donepezil and cilostazol (n = 34; 77.2±6.8 years old), the annual change in MMSE score was −0.5±1.6 during an observational period of 28.6±11.7 months, with those receiving donepezil only (n = 36; 78.4±6.5 years old) scoring less (−2.2±4.1) during 30.4±12.8 months with a statistical intergroup difference (p = 0.022). Multivariate analysis showed that absence of cilostazol treatment was the only significant predictor of MMSE decline. A positive effect of cilostazol was found in three subscale scores of MMSE, orientation for time or place and delayed recall. By clear contrast, in patients with moderate/severe dementia, there were no intergroup differences in decrease of total or subscale MMSE scores between the two groups.ConclusionsThese results suggest potential for cilostazol treatment in the suppression of cognitive decline in patients receiving donepezil with mild dementia but not in those with moderate/severe dementia.

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

“…for the prevention of stroke or peripheral artery disease) reported that average daily doses above 100 mg for at least 6 months improved MMSE scores in MCI patients [38] and mild AD patients as add-on to 10 mg donepezil per day [39]. The same research group at the National Cerebral and Cardiovascular Center Hospital (Osaka, Japan) has started a new study investigating the effects on MMSE scores of cilostazol 50 mg twice a day for 96 weeks in patients with MCI (ClinicalTrials.gov identifier: NCT02491268).…”

Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart

“…In the present study, we focused on the interaction of donepezil and cilostazol at efflux transporters as a potential explanation of the clinically reported cardiotoxicity of donepezil when coadministered with cilostazol (Tanaka et al, 2009;Shinozaki, 2012;Igeta et al, 2013). This is an important issue because simultaneous use of donepezil and cilostazol has been proposed to improve the pharmacologic outcome (Lee et al, 2007;Ihara et al, 2014).…”

“…However, the mechanism of the putative drug-drug interaction (DDI) has not yet been clarified, even though donepezil is often administered with other drugs, as it is frequently prescribed for elderly people. On the other hand, it has been proposed that coadministration of donepezil with cilostazol is more effective in patients with mild dementia (Ihara et al, 2014), and this has been supported by findings in an animal model (Lee et al, 2007). Accordingly, it is important to examine whether interaction of donepezil with cilostazol might occur, and if it does, whether it might have clinical relevance.…”

Management of Alzheimers Disease: Role of Existing Therapies, Traditional Medicines and New Treatment Targets

“…Cilostazol, an antiplatelet agent with pleiotropic effects based on phosphodiesterase-3-dependent mechanisms was studied for its use in management of AD [90] . A retrospective analysis of cilostazol as an addon therapy in patients with mild dementia receiving donepezil shown to suppress the cognitive decline [90,91] .…”

“…A retrospective analysis of cilostazol as an addon therapy in patients with mild dementia receiving donepezil shown to suppress the cognitive decline [90,91] . Prospective randomized controlled trials (RCT) are required to validate these results.…”