Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

BACKGROUND: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Neuroprotective effects of clarithromycin against neuronal damage in cerebral ischemia and in cultured neuronal cells after oxygen-glucose deprivation.

AIMS: Rats subjected to transient focal ischemia and cultured neuronal cells subjected to oxygen-glucose deprivation (OGD) were treated with clarithromycin (CAM) to evaluate the effects of CAM in protecting against neuronal damage. MAIN METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90min and then reperfused. Each animal was given an oral dose clarithromycin (CAM, 100mg/kg) or vehicle alone just after the ischemia was commenced. The infarct volume, edema index and neurological performance were assessed after 24 and 72h of reperfusion. The cerebral blood flow (CBF) was measured with an MRI system at 90min after MCAO. After 24 and 72h, oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) were assessed by immunohistochemical analyses and degenerative cells were assessed in the cortex by Fluoro-Jade C (FJC) labeling. The cultured neuronal cells were also used to examine the effects of CAM exposure on the viability of the cells after OGD. KEY FINDINGS: CBF was unchanged between the two groups. Significant reductions of the infarct volume and edema index, an improved neurological deficit score, a significant suppression of 4-HNE and 8-OHdG expression, marked reductions of Iba-1 and TNF-α expression, and a significant reduction of FJC-positive cells were also observed in the CAM-treated animals at both time points. Treatment with 10µM and 100µM CAM in vitro significantly reduced cell death after OGD. SIGNIFICANCE: CAM appears to provide antioxidant and anti-inflammatory effects and protect against neuronal damage after cerebral ischemia and OGD.

High urinary albumin/creatinine ratio at admission predicts poor functional outcome in patients with acute ischaemic stroke.

AIM: Albuminuria and a low estimated glomerular filtration rate (eGFR) are widely recognized indices of kidney dysfunction and have been linked to cardiovascular events, including stroke. We evaluated albuminuria, measured using the urinary albumin/creatinine ratio (UACR), and the eGFR in the acute phase of ischaemic stroke, and investigated the clinical characteristics of ischaemic stroke patients with and those without kidney dysfunction. METHODS: The study included 422 consecutive patients admitted between June 2010 and May 2012. General blood and urine examinations were performed at admission. Kidney dysfunction was defined as a low eGFR (<60 mL/min per 1.73 m2 ), high albuminuria (≥30 mg/g creatinine), or both. Neurological severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) at admission and the modified Rankin scale (mRS) at discharge. A poor outcome was defined as a mRS score of 3-5 or death. The impacts of the eGFR and UACR on outcomes at discharge were evaluated using multiple logistic regression analysis. RESULTS: Kidney dysfunction was diagnosed in 278 of the 422 patients (65.9%). The eGFR was significantly lower and UACR was significantly higher in patients with a poor outcome than in those with a good outcome. In multivariate analyses performed after adjusting for confounding factors, UACR >31.2 mg/g creatinine (OR, 2.58; 95% CI, 1.52-4.43; P = 0.0005) was independently associated with a poor outcome, while a low eGFR was not associated. CONCLUSIONS: A high UACR at admission may predict a poor outcome at discharge in patients with acute ischaemic stroke.

Neuroprotective effects of erythromycin on ischemic injury following permanent focal cerebral ischemia in rats.

OBJECTIVE: This study aims to determine if erythromycin provides neuroprotective effects against ischemic injury following permanent focal cerebral ischemia. METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Each animal received a single subcutaneous injection of erythromycin lactobionate (EM, 50 mg/kg) or vehicle immediately after ischemia. The infarct volume, edema index and neurological performance were evaluated at 24 and 72 h after MCAO. The cerebral blood flow (CBF) was measured with an MRI system at 30 min after MCAO. TUNEL staining and immunohistochemical analyses for oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) in the cortex were conducted at 24 and 72 h after MCAO. RESULTS: The CBF did not differ between the EM-treated and vehicle-treated groups. The EM treatment significantly reduced the infarct volume (p < 0.01) at 24 and 72 h after MCAO and significantly reduced the edema index (p < 0.01) at 24 h. The EM treatment significantly improved the neurological deficit scores (p < 0.05) at 24 and 72 h. EM also significantly suppressed the accumulation of 4-HNE (p < 0.01) and 8-OHdG (p < 0.01) and markedly reduced Iba-1 (p < 0.01) and TNF-α expression (p < 0.05) at both time points. The EM treatment significantly reduced TUNEL-positive cells (p < 0.01) at both time points. CONCLUSION: These findings suggest that EM can protect against the neuronal damage caused by cerebral ischemia by alleviating inflammation and reducing oxidant stress.

Cardiovascular events occur independently of high on-aspirin platelet reactivity and residual COX-1 activity in stable cardiovascular patients.

Several studies have indicated that approximately 25 % of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B2 or urinary 11-dehydro TXB2. Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8 %). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients.

Effects of Candesartan Cilexetil Compared with Amlodipine on Serum Asymmetric Dimethylarginine Levels in the Chronic Stage of Cerebral Infarction: A Preliminary Study.

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor and a marker of vascular endothelial damage. Angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker (ARB) are reported to reduce the serum ADMA level. Our group administered either ARB or calcium antagonist to patients after cerebral infarction and discussed the ADMA changes observed. METHODS: Hypertensives in the chronic stage of cerebral infarction were enrolled. These subjects included patients of atherothrombotic cerebral infarction or lacunar infarction. The patients received candesartan cilexetil (candesartan group) or amlodipine (amlodipine group). The blood pressure and serum ADMA concentration were measured and compared before the treatment commenced and at 1-3 months after the treatment commenced. RESULTS: Seven subjects received candesartan and six received amlodipine. There was no difference between the groups in the change of blood pressure before and after the drug treatment. The ADMA level (nmol/mL) fell significantly from 0.57±0.10 (before administration) to 0.52±0.09 (after administration) in the candesartan group (P<0.05). The ADMA level did not change between before and after administration in the amlodipine group. CONCLUSION: Treatment with candesartan cilexetil reduced the level of ADMA in hypertensive patients in the chronic stage of cerebral infarction. Candesartan cilexetil may be useful in hypertensive patients at the chronic stage of cerebral infarction with expected anti-atherosclerotic effect.

Long-term observation of lateral medullary infarction due to vertebral artery dissection assessed with multimodal neuroimaging.

A 33-year-old man presented with a lateral medullary infarction, vertigo, and nausea. At the time of hospital admission, he had Wallenberg syndrome. Although initial magnetic resonance imaging showed no abnormalities, subsequent diffusion-weighted magnetic resonance imaging showed a high-intensity area in the right lateral medulla oblongata. The right vertebral artery was shown to be dilated on basi-parallel anatomical scanning but to be stenosed on magnetic resonance angiography (MRA). Cerebral angiography 7 days after onset showed the "pearl and string sign" in the right vertebral artery. Follow-up MRA showed gradual improvement of the stenosis in the right vertebral artery. Multiple neuroimaging studies, such as MRA, basi-parallel anatomical scanning, 3-dimensional computed tomographic angiography, and cerebral angiography, should be performed soon after onset in suspected cases of cerebral artery dissection. In addition, serial imaging examinations increase diagnostic accuracy, and the medical history and neurological examination are important.

Neuroprotective effects of pretreatment with macrolide antibiotics on cerebral ischemia reperfusion injury.

OBJECTIVE: This study aims to determine if macrolide antibiotics have neuroprotective effects against transient cerebral ischemia. METHODS: Sprague-Dawley rats were subjected to cerebral ischemia for 90 minutes followed by 24 or 72 hours of reperfusion. An oral suspension of roxithromycin (RXM), clarithromycin (CAM), erythromycin (EM), azithromycin (AZM), or kitasamycin (INN) was given at 10 or 100 mg/kg for 7 days before ischemia. The infarct volume, edema volume, and neurological performance were evaluated after 24 and 72 hours of reperfusion. The cerebral blood flow (CBF) was measured with a magnetic resonance imaging (MRI) system after 90 minutes of ischemia. Another experiment was conducted to investigate how the ischemic injury was affected by the interval from the antibiotic pretreatment to the ischemia in rats pretreated with CAM. RESULTS: Roxithromycin, CAM, AZM, and INN significantly reduced the infarct volume in the high-dose group after 24 and 72 hours of reperfusion. All of the agents significantly decreased the edema in the high-dose groups at 24 and 72 hours, while only CAM and AZM significantly reduced the edema volume in the low-dose groups at 24 hours. All of the macrolide antibiotics at the high dose significantly improved neurological deficit scores at 24 and 72 hours. There were no differences in the CBF between the vehicle and respective antibiotic groups. In the experiment examining the interval, the 24-hour interval group exhibited the strongest neuroprotective effect. DISCUSSION: These results demonstrate that the macrolide antibiotics RXM, CAM, EM, AZM, and INN may confer neuroprotective effects against ischemic damage following cerebral ischemia without affecting the CBF.

Therapeutic effects of the long-term use of PAN membrane dialyzer in hemodialysis patients: efficacy in old dialysis patients with mild PAD.

BACKGROUND: AN69 dialyzer, a plate type dialyzer with a polyacrylonitrile membrane (PAN membrane) is reported to reduce symptoms in hemodialysis (HD) patients with complications such as poor nutritional status and peripheral arterial disease (PAD). Yet very few studies have investigated the long-term use of the PAN membrane or compared the solute-removal properties of the PAN membrane with those of the Type IV polysulfone membrane (PS membrane), the dialysis membrane most widely used. In the present study we compared the contaminant-removal properties of the AN69 membrane dialyzer with those of a Type IV PS membrane dialyzer and investigated the clinical effects of the long-term use of the former for elderly hemodialysis patients with mild PAD. METHODS: Cross-over trials with 2 week intervals for solute were conducted in 6 patients to compare the performance of the membranes in removing small molecular weight substances, ß2 microglobulin (ß2MG), amino acid (AA), and serum albumin (Alb). Next, the AN69 membrane was used for dialysis over a period of 72 weeks in 8 patients. The time course changes of Alb, the geriatric nutritional risk index (GNRI), the % creatinine generation rate (%CGR), the normalized protein catabolic rate (nPCR) and the dry weight (DW) were observed to evaluate the nutritional status. The time course changes of ß2MG, C-reactive proteins (CRP), LDL cholesterol (LDL), fibrinogens (Fib), nitrogen oxide (NOx), hemoglobin (Hb), ferritins, transferrin saturation (TSAT), dose of erythropoiesis-stimulating agents (ESA), and dose of iron were observed to evaluate the therapeutic effects of long-term use. Skin perfusion pressure (SPP) was measured at two points: once at the switchover to the AN69 membrane and once 72 weeks later. RESULTS: In cross-over trials, the AN69 membrane showed basically the same dialysis efficiency as the PS membrane in removing small molecular weight substances, but it removed significantly lower amounts of ß2MG. The AN69 membrane also showed significantly lower rates of AA removal rate and Alb leakage. The nutritional status was stably maintained during long-term use after the switchover to the AN69 membrane, and no significant increase of ß2MG was observed. Fib and NOx were both reduced, the latter to a significant degree. The Hb values showed a good time course, with relatively high TSAT levels and low ferritin levels overall. SPP remained generally stable for 72 weeks. CONCLUSION: The cross-over trial show the AN69 membrane eliminates less AA and Alb compared with the PS membrane. Judging from the therapeutic effects of the long-term use of the AN69 membrane, the membrane is effective for dialysis and has good biocompatibility in the treatment of elderly HD patients with mild PAD.

Efficacy of tracheostomy for central alveolar hypoventilation syndrome caused by lateral medullary infarction.

Central alveolar hypoventilation syndrome (CAHS) is a rare and potentially fatal condition. However, respiratory care for patients with CAHS caused by lateral medullary infarction (CAHS-LMI) remains an important unsolved problem. We describe 2 patients with CAHS-LMI and review the case reports for 17 previously described patients. Patient 1 was a 78-year-old man who was referred to our hospital because of dizziness. After admission, Wallenberg syndrome developed. Magnetic resonance imaging showed left LMI. He had hypercapnia and respiratory acidosis the next afternoon and temporarily received mechanical ventilation. A tracheotomy was performed on the 12th hospital day, and the patient was weaned from the ventilator on the 18th hospital day. Patient 2 was 72-year-old man who was referred to our hospital because of dizziness and gait disturbance. Wallenberg syndrome was diagnosed after admission, and magnetic resonance imaging showed right LMI. His consciousness deteriorated, and hypercapnia developed on the ninth hospital day. The patient received ventilatory support, and a tracheotomy was performed on the 12th hospital day. He was weaned from the ventilator by the 16th hospital day. Consistent with our findings, most previously reported cases of CAHS-LMI were initially associated with mild symptoms, which subsequently worsened. Five of the 19 patients (26.3%) died within 1 month after onset, and 7 patients (36.8%) died within 1 year. Tracheotomy was performed in 12 patients, 2 of whom died 1 month after onset (16.7%); another patient died of chronic renal failure after 2 years. Tracheotomy seemed to be an effective procedure in patients with CAHS-LMI. We speculate that tracheotomy assists alveolar ventilation by reducing dead space ventilation. Closure of the tracheotomy should, therefore, be avoided in patients with CAHS-LMI, even if respiratory status is good.

Neuroprotective effects of erythromycin on cerebral ischemia reperfusion-injury and cell viability after oxygen-glucose deprivation in cultured neuronal cells.

This study aims to determine if erythromycin has neuroprotective effects against transient ischemia and oxygen-glucose deprivation (OGD) in cultured neuronal cells. Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion. The animals received a subcutaneous single injection of erythromycin lactobionate (EM, 50mg/kg) or vehicle immediately after ischemia. Infarct volume, edema index, and neurological performance were evaluated at 24 and 72 h after reperfusion. Immunohistochemical analyses for oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) were conducted in the cortex at 24h. Primary cortical neuronal cell cultures were prepared from the cerebral cortices of the animals and then subjected to OGD for 3h. Ten or 100 µM EM was added before OGD to determine the effect of EM on cell viability after OGD. EM significantly reduced infarct volume (p<0.01) and edema volume (p<0.05) and improved neurological deficit scores (p<0.05) at 24 and 72 h. EM significantly suppressed the accumulation of 4-HNE (p<0.01) and 8-OHdG (p<0.01) and markedly reduced Iba-1 (p<0.01) and TNF-α expression (p<0.01). Treatment with 100 µM EM in vitro significantly reduced cell death after OGD. EM reduces neuronal damage following cerebral ischemia and OGD and may have antioxidant and anti-inflammatory effects.

Relative risk values of age, acrolein, IL-6 and CRP as markers of periventricular hyperintensities: a cross-sectional study.

OBJECTIVE: Brain white matter hyperintensities can be divided into periventricular hyperintensity (PVH) and deep-and-subcortical white matter hyperintensity (DSWMH); the former contributes more to cognitive dysfunction and infarction risk. We conducted the present investigation to define the relationship between PVH and DSWMH. DESIGN: Cross-sectional study. SETTING: University hospital. PARTICIPANTS: We prospectively enrolled 228 healthy Japanese volunteers with relative risk values (RRVs) >0.5. PRIMARY OUTCOME MEASURES: We investigated whether it is possible to use the RRV to predict PVH and DSWMH. RESULTS: Among 228 volunteers, 103 (45.1%) and 157 (68.8%) exhibited PVH and DSWMH, respectively. Age, body mass index and PVH were significant independent determinants of RRV. A significant OR for PVH was noted in the highest RRV tertile compared with the lowest, after adjusting for potential confounding factors. A significant OR for high predicted PVH risk was found for RRV levels as well. CONCLUSIONS: Elevated RRV levels were significantly associated with increased predicted PVH, suggesting that measuring the plasma protein-conjugated acrolein, interleukin 6 and C reactive protein levels may be useful for identifying Japanese at high risk for PVH.

Early identification of cognitive impairment and dementia: Results from four years of the community consultation center.

The community consultation center was established as the core facility for a project entitled "Community Support Network for Citizens with Mild Cognitive Impairment (MCI) and Dementia." This study reports on our center's activity and user outcomes. Users consulted with medical staff regarding their memory problems and were self-screened using a touch-panel computer assisted screening tool (TPST). Dementia was suspected when the TPST score was 12 points or below, and the Mini-Mental State Examination (MMSE) was conducted by our onsite clinical psychologists, which served as the gold standard. All reports were provided to user's primary care physicians, or a nearby medical institute if users did not have a primary care physician. Patient outcomes were obtained from participating medical institutes. Informed consent was obtained for all users. In the four-year period, 2802 users visited the center. Of them, 1565 registered (men/women=519/1046; mean age, 74 years). Of 1354 people who used TPST, 622 (45.9%) scored 12 points or below. 409 confirmed diagnoses from the medical institutes revealed MCI in 11.2%, Alzheimer's disease in 37.1%, and vascular dementia in 8.0%. Among the 207 users who had no primary care physicians at consultation, 43 (20.8%) were diagnosed with MCI or dementia. Approximately half of the users who took the TPST were suspected of dementia following interview by a clinical psychologist. Both MCI and dementia were confirmed by the medical institutes in 59.6% of users. We conclude that our consultation center plays a pivotal role in early diagnosis of MCI and dementia.

Acute vertebral artery origin occlusion leading to basilar artery thrombosis successfully treated by angioplasty with stenting and thrombectomy.

Few reports have described the successful treatment of stroke caused by acute vertebral artery (VA) origin occlusion by endovascular surgery. We describe the case of a 68-year-old man who experienced stroke due to left acute VA origin occlusion. Cerebral angiography showed that the left VA was occluded at its origin, the right VA had hypoplastic and origin stenosis, and the basilar artery was occluded by a thrombus. The VA origin occlusion was initially passed through with a 0.035-inch guide wire. An angioplasty was performed, and a coronary stent was appropriately placed. The VA origin was successfully recanalized. A balloon-assisted guiding catheter was navigated through the stent and a thrombectomy was performed using the Penumbra system. The patient's symptoms gradually improved postoperatively. Balloon-assisted catheter guidance through a vertebral artery stent permitted a successful thrombectomy using the Penumbra system and may be useful for treating stroke due to VA origin occlusion.

Excision of Zenker's diverticulum to treat dysphagia associated with acute-phase cerebral infarction.

A 75-year-old man was admitted to our hospital with dysphagia shortly after the onset of a brainstem infarction. Videofluorography indicated the presence of a Zenker's diverticulum with a bolus at the esophageal orifice; endoscopy 5 years earlier had not shown a Zenker's diverticulum and suggests that the diverticulum had formed because of an increase in the hypopharyngeal pressure caused by the brainstem infarction. Surgical excision successfully facilitated transport of the bolus to the esophageal orifice. In the present report, we describe a case of dysphagia caused by a Zenker's diverticulum following and associated with a brain infarction.

Aortic arch atherosclerosis in ischaemic stroke of unknown origin affects prognosis.

BACKGROUND: Cerebral infarction of unknown origin at admission accounts for half of all cerebral infarction cases in some institutions. However, the factors associated with cerebral infarction prognosis have not been sufficiently examined. Here, we investigated whether aortic arch plaques (AAPs) on transoesophageal echocardiography (TOE) were associated with the prognosis of cerebral infarction of unknown origin at admission. METHODS: Of 571 patients who were hospitalised between June 2009 and September 2011, 149 (age: 67 ± 14 years; 95 men) with cerebral infarctions of unknown origin at admission underwent TOE and were enrolled in this study. We examined their clinical characteristics, the incidence of intermittent atrial fibrillation detected on 24-hour electrocardiography, and the echographic findings of the carotid artery in the hospital. A poor prognostic outcome was defined as a modified Rankin Scale score of ≥3 after 90 days. RESULTS: In all, 110 patients (74%) showed good prognoses and 39 patients (26%) showed poor outcomes. A National Institutes of Health Stroke Scale score of >6 on admission [odds ratio (OR) = 6.77; 95% confidence interval (CI): 2.59-18.8; p < 0.001] and AAPs of ≥4 mm (OR = 2.75; 95% CI: 1.19-6.91; p = 0.024) showed significant associations with a poor prognosis of cerebral infarction of unknown origin at admission. CONCLUSIONS: Thick AAPs could be a factor in the prediction of a poor prognosis of cerebral infarction of unknown origin at admission. The establishment of international standards for aortogenic brain embolisms is required. Future prospective studies should examine cerebral infarctions of unknown origin.

The effect of cilostazol and aspirin pre-treatment against subsequent transient focal cerebral ischemia in rat.

OBJECTIVES: Among several anti-platelet drugs to prevent recurrent stroke, cilostazol has shown various effects besides its anti-platelet activity. We examined whether 7 days of oral administration of cilostazol protects against subsequent cerebral ischemia, and whether or not the effect of combination therapy with aspirin is more protective. METHODS: We used Sprague-Dawley (SD) rats and assigned them to four groups: vehicle, aspirin, cilostazol, and aspirin plus cilostazol combination therapy. After oral administration of anti-platelets for 7 days, we performed transient middle cerebral artery occlusion (MCAO) for 90 minutes, and examined infarct volume, neurological symptoms, and regional cerebral blood flow (rCBF). Immunostaining of Bax, Bcl-2, TUNEL, 4-HNE, 8-OHdG, and COX-2 was performed 24 hours after ischemia. RESULTS: The cilostazol group and the combination therapy group showed significant decreases of infarct volume and significant improvements of rCBF during ischemia, compared with the vehicle or aspirin group. Significant decreases of Bax, TUNEL, 8-OHdG, and 4-HNE expression in the combination therapy group, compared with those in the vehicle or aspirin group, were shown in the boundary zone. COX-2 expression was unexpectedly increased in the combination therapy group. DISCUSSION: Aspirin co-administration did not inhibit this effect. The addition of the oral administration of cilostazol either alone or with aspirin administration may be beneficial for subsequent cerebral ischemic damage in terms of reducing infarct volume, improving rCBF during ischemia, inhibiting the apoptotic pathway, and reducing oxidative stress.

Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

The potentially protective effect of donepezil in Alzheimer's disease.

BACKGROUND/AIMS: Donepezil is an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD). In this study, we used a voxel-based specific regional analysis system for AD (VSRAD) to analyze the hippocampal volume and to assess the pharmacologic effects of donepezil as a disease modifier. METHODS: A total of 185 AD patients underwent MRI, 120 (43 men and 77 women, 77.8 ± 7.1 years) without and 65 (29 men and 36 women, 78.4 ± 6.0 years) with donepezil treatment. VSRAD was compared in both groups and against a database of 80 normal subjects. The Z-score was used to assess the degree of hippocampal atrophy. RESULTS: No significant difference between the groups was found for age, sex, or Z-scores, but a significant difference was found for mean Mini-Mental State Examination (MMSE) scores (p = 0.02, Student's t test). Single regression analysis showed no significant association between Z-scores and MMSE scores in the treated group (p = 0.494), but a significant association in the untreated group (p = 0.001) was observed. This implies that the MMSE score becomes lower when the Z-score is higher in the untreated group, whereas there is no significant trend in the treated group. CONCLUSION: Donepezil affects the relationship between hippocampal volume and cognitive function and may therefore have a pharmacologic effect as a disease modifier.