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

Saitô, Satoshi; Shinmyozu, Kaori; Kawakami, Daisuke; Yamauchi, Miho; Ikeda, Shuhei; Hattori, Yorito; Yamamoto, Rintaro; Hayakawa, Naoki; Ihara, Masafumi

doi:10.1002/trc2.12182

Cited by 5 publications

(4 citation statements)

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“…Selecting the MMSE as the primary end point was mainly due to the lack of clinical studies using assessments other than the MMSE to evaluate cilostazol’s association with cognition when the present study was initially planned. However, a recent study by some of us reported that transitioning from cilostazol to 3,4-dehydrocilostazol was associated with preserving cognitive function, as evaluated by the Montreal Cognitive Assessment. Mild cognitive impairment is a complex condition encompassing various pathological factors, including vascular diseases; therefore, neuropsychological tests more sensitive to information-processing speed and executive function may be needed in future trials.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that cilostazol may be effective for treating patients with dementia. Several studies have examined the beneficial effects of cilostazol on cognitive impairment, but the results are inconsistent . To our knowledge, clinical trials specifically targeting patients with neurocognitive disorders who do not have a history of stroke have yet to be conducted.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have examined the beneficial effects of cilostazol on cognitive impairment, but the results are inconsistent. 27 , 28 , 29 , 30 , 31 , 32 To our knowledge, clinical trials specifically targeting patients with neurocognitive disorders who do not have a history of stroke have yet to be conducted. We therefore conducted a randomized clinical trial to assess the safety and efficacy of cilostazol in patients with mild cognitive impairment (MCI).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and Safety of Cilostazol in Mild Cognitive Impairment

Saito,

Suzuki,

Ohtani

et al. 2023

JAMA Netw Open

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ImportanceRecent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage.ObjectiveTo determine the safety and efficacy of cilostazol in mild cognitive impairment.Design, Setting, and ParticipantsThe COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020.InterventionsThe participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks.Main Outcomes and MeasuresThe primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events.ResultsThe full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were –0.1 (0.3) at the 24-week visit, –0.8 (0.3) at 48 weeks, –1.2 (0.4) at 72 weeks, and –1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were –0.6 (0.3) at 24 weeks, –1.0 (0.3) at 48 weeks, –1.1 (0.4) at 72 weeks, and –1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically.Conclusions and RelevanceIn this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials.Trial RegistrationClinicalTrials.gov Identifier: NCT02491268

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy and Safety of Cilostazol in Mild Cognitive Impairment

Saito,

Suzuki,

Ohtani

et al. 2023

JAMA Netw Open

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“…Genotyping of RNF213 p.R4810K was performed using a fully automated gene analysis system (GTS-7000; Shimadzu Corporation, Kyoto, Japan or LightCycler 96 system; Roche, Basel, Switzerland). These systems allow the direct detection of single-nucleotide polymorphisms from 1 µL of whole blood samples using real-time polymerase chain reaction 15) . The primer sequences used in the current analysis were 5'-TTCCAGAACGTCCAGCAAGT-3' (forward) and 5'-ACAGTCCTGGTCCTGTCAGA-3'…”

Section: Rnf213 Genotyping Examinationmentioning

confidence: 99%

<i>RNF213</i> p.R4810K Variant Carriers with Intracranial Arterial Stenosis Have a Low Atherosclerotic Burden

Ohara

Yoshimoto

Okazaki

et al. 2022

JAT

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The ring finger protein 213 gene (RNF213) p.R4810K variant is a major susceptibility gene for intracranial arterial stenosis in East Asia. We hypothesized that if intracranial arterial stenosis is induced by a non-atherosclerotic mechanism similar to moyamoya disease, the patients with RNF213 p.R4810K variant may have a lower cumulative atherosclerotic burden than the non-carriers. Methods: A total of 112 participants with intracranial arterial stenosis were enrolled in this multicenter crosssectional study. We compared the prevalence of atherosclerotic risk factors and three different cardiovascular risk scores (Essen Stroke Risk Score, Framingham Risk Score, and Suita Risk Score) between the RNF213 p.R4810K variant carriers and non-carriers. Patients with moyamoya disease were excluded from the study. Results: The RNF213 p.R4810K variant carriers were younger than the non-carriers (P＜0.001). The prevalence of each atherosclerotic risk factor was not significant, but it tended to be lower in the variant carriers. The Essen Stroke Risk Score (carriers: 2.3±1.5 vs. non-carriers: 2.9±1.5, P=0.047), Framingham Risk Score (10.7±6.4 vs. 15.3±6.2, P = 0.001), and Suita Risk Score (35.4±15.8 vs. 48.7±15.2, P＜0.001) were significantly lower in the variant carriers. Among the three risk scores, the Suita score showed the highest predictive accuracy for the variant carriers. Conclusions: RNF213 p.R4810K variant carriers have a lower cumulative atherosclerotic burden than noncarriers among patients with intracranial arterial stenosis. New therapeutic approaches beyond the standard management of atherosclerotic risk factors are required to prevent the development of intracranial arterial stenosis.susceptibility gene for moyamoya disease 3, 4) , was found to be a strong risk factor for intracranial arterial stenosis 5, 6) and ischemic stroke 7) . Approximately 22%-50% of patients with intracranial arterial stenosis reportedly have this variant 5, 6) , which is much higher than the prevalence in the general populationCopyright©2021 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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Association of the RNF213 p.R4810K Variant With the Outer Diameter of Cervical Arteries in Patients With Ischemic Stroke

Yamaguchi

Yoshimoto

Ogura

et al. 2022

SVIN

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BACKGROUND We investigated the impact of the p.R4810K variant of RNF213 (ring finger protein 213) gene, a susceptibility gene of moyamoya disease in East Asia, on the outer diameter of cervical parts of carotid and vertebral arteries (VAs). METHODS We examined consecutive Japanese patients with ischemic stroke who underwent carotid ultrasonography between 2015 and 2019. Patient background and the carotid ultrasonography‐measured outer diameter of extracranial cervical arteries, including the common carotid artery, internal carotid artery, external carotid artery, and cervical VA, were compared between variant carriers and noncarriers. Outer diameters of each artery were defined as the mean distance from far to near wall adventitia of right and left target arteries using carotid ultrasonography. The average diameter of both cervical portions of common carotid arteries, internal carotid arteries, external carotid arteries, and the dominant side diameter of both cervical VAs were used. RESULTS Of the 617 adult patients (204 women; median age, 74 years) analyzed, 26 (4.2%) carried the RNF213 p.R4810K variant. Variant carriers were significantly younger ( P <0.01) and had more frequent steno‐occlusion of the M1 segment of the middle cerebral artery ( P <0.01). Multivariate logistic regression analysis showed that variant carriers had significantly smaller mean diameters in the common carotid artery (7.25 versus 8.22 mm; adjusted odds ratio [aOR] per 1 mm decrease, 2.94; 95% CI, 1.69–5.00), cervical internal carotid artery (4.99 versus 5.55 mm; aOR, 1.66; 95% CI, 1.03–2.70), and cervical VA (3.55 versus 4.10 mm; aOR, 2.56; 95% CI, 1.33–4.76) than noncarriers. Mean diameters of the common carotid artery (aOR, 3.44; 95% CI, 2.08–5.88) and cervical internal carotid artery (aOR, 2.04; 95% CI, 1.23–3.33) and the dominant diameter of the cervical VA (aOR, 3.23; 95% CI, 1.72–5.88) were also smaller in variant carriers even when the analysis was restricted to patients without bilateral steno‐occlusion in target vessels or intracranial arteries distal to target vessels. CONCLUSION RNF213 p.R4810K variant carriers have smaller cervical arterial outer diameters in both anterior and posterior circulations than noncarriers with ischemic stroke. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02251665.

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

Cited by 5 publications

References 40 publications

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment

<i>RNF213</i> p.R4810K Variant Carriers with Intracranial Arterial Stenosis Have a Low Atherosclerotic Burden

Association of the RNF213 p.R4810K Variant With the Outer Diameter of Cervical Arteries in Patients With Ischemic Stroke

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