Conversion from cilostazol to OPC-13015 linked to mitigation of cognitive impairment

Abstract

Introduction: Cilostazol may be a novel therapeutic agent for Alzheimer's disease. Its metabolite, OPC-13015, has a stronger inhibitory effect on type 3 phosphodiesterase than cilostazol.

Methods: We prospectively enrolled patients with mild cognitive impairment to whom cilostazol was newly prescribed. Patients underwent the Montreal Cognitive Assessment (MoCA) twice, at a 6-month interval. Plasma cilostazol, OPC-13015, OPC-13213, and OPC-13217 concentrations were determined using liquid chromatography-tandem mass spectrometry.

Results: MoCA score changes from baseline to the 6-month visit were positively correlated with ratios of OPC-13015 to cilostazol and total metabolites (n = 19, P = .005). Patients with higher ratios of OPC-13015 (≥0.18, median value; n = 10) had significantly higher MoCA scores (P = .036) than patients with lower ratios (the ratio <0.18, n = 9). The absolute value of OPC-13015 concentration in blood was also higher in patients with preserved cognitive function (P = .033).

Discussion: Blood OPC-13015 levels may be a predictive biomarker of cilostazol treatment for Alzheimer's disease.

Keywords: Alzheimer's disease; OPC‐13015; cilostazol; drug repositioning; mild cognitive impairment; stratified medicine.

FIGURE 1

Chemical structural formulae of cilostazol and its metabolites. The major metabolites of cilostazol (OPC‐13013) are 3,4‐dehydrocilostazol (OPC‐13015) and 4′‐trans‐hydroxycilostazol (OPC‐13213). In rats, 4‐cis‐hydroxycilostazol (OPC‐13217) is also detected in the blood, but OPC‐13217 levels are relatively low in humans. Because of the difficulty of measuring the concentrations of OPC‐13213 and OPC‐13217 separately, the total amounts of OPC‐13213 and OPC‐13217 were estimated in this study

FIGURE 2

Measurements of the levels of cilostazol and its metabolites. Representative chromatograms of cilostazol, OPC‐13015, and OPC‐13213/13217 in cilostazol standard solution (A‐C), OPC‐13015 standard solution (D‐F), or blood samples from a subject receiving cilostazol (G‐I). The peak for cilostazol was detected in (A), but was not detected using the settings for the measurement of OPC‐13015 (B) or OPC‐13213/13217 (C). The peak for OPC‐13015 was detected in (E), but was not detected using the settings for the measurement of cilostazol (D) or OPC‐13213/13217 (F). Cilostazol (G), OPC‐13015 (H), and OPC‐13213/13217 (I) were detected in blood samples from a subject receiving cilostazol. MRM, multiple reaction monitoring

FIGURE 3

Study design. CDR, Clinical Dementia Rating; MoCA, Montreal Cognitive Assessment

FIGURE 4

Scatter plots showing the levels of cilostazol and metabolites. Time between the last dose and blood sampling was not associated with the levels of cilostazol (A, Spearman's rho = −0.059), OPC‐13015 (B, Spearman's rho = 0.083), or OPC‐13213 and OPC‐13217 (OPC‐13213/13217) (C, Spearman's rho = −0.026) in patients receiving 100 mg (filled circles) or 200 mg (filled squares) per day of cilostazol. Large individual differences were observed in the concentrations of cilostazol and its metabolites

FIGURE 5

Amelioration of cognitive impairment was related to high OPC‐13015 levels. A, Mean scores in the Montreal Cognitive Assessment (MoCA) were increased in the higher OPC‐13015 group (filled circles, n = 10) compared with the lower group (filled squares, n = 9). Two‐way repeated‐measures analysis of variance; error bars indicate the standard errors. B, The ratio of OPC‐13015 to total analytes was positively correlated with the changes in MoCA from baseline to follow‐up (n = 19, Spearman's rho = 0.617). C‐E, Box‐and‐whisker plots showing the median, quartiles, maximum, and minimum of the ratio of cilostazol and its metabolites. Mann‐Whitney U test. The cilostazol ratio was slightly lower in patients with cognitive preservation (n = 11; change in MoCA from baseline to follow‐up ≥ 0) compared with those without cognitive preservation (n = 8; change in MoCA from baseline to follow‐up < 0) (C). The OPC‐13015 ratio was significantly higher in patients with cognitive preservation (D), whereas the OPC‐13213/13217 ratio was not significantly different between the two groups (E)