Akiro Terashi

Cilostazol Stroke Prevention Study: A Placebo-Controlled Double-Blind Trial for Secondary Prevention of Cerebral Infarction

Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P=.0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P=.0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction.

Role of the Nondominant Hemisphere and Undamaged Area During Word Repetition in Poststroke Aphasics: A PET Activation Study

BACKGROUND AND PURPOSE Although the resting regional cerebral blood flow (rCBF) in aphasic patients has been thoroughly investigated with positron emission tomography (PET) and single-photon emission CT, and PET studies in normal subjects have elucidated the functional localization of language processing, little is known about the activation pattern of language processing in aphasic patients. METHODS We measured the changes in rCBF during a repetition task (hearing a single word and repeating it aloud) and the resting state using the H2(15)O PET activation technique in 6 normal subjects (mean +/- SD age, 58.3 +/- 8.1 years) and 16 aphasic patients: 10 fluent aphasics (age, 60.3 +/- 12.5 years) and 6 nonfluent aphasics (age, 50.5 +/- 8.3 years). RESULTS In normal subjects, the posteroinferofrontal area (PIF) including Brocas area, the posterosuperotemporal area (PST) including Wernickes area, the rolandic areas, and a few other areas were activated with left side dominance by the repetition task. In the resting state, the rCBF in the left PIF and the left posterotemporal area was reduced in both fluent and nonfluent aphasics. In aphasic patients, the magnitude of activation in the right PIF and PST by the repetition task was greater than in normal subjects. The increase in rCBF during the repetition task in the left PIF correlated with the Western Aphasia Battery score of spontaneous speech in the nonfluent aphasics with a left inferofrontal lesion. CONCLUSIONS This study shows the importance in aphasic patients of the mirror regions of the left PIF and PST in the nondominant (right) hemisphere for performing the word repetition task. The results also show the importance for nonfluent aphasic patients of the recruitment of the undamaged PIF for spontaneous speech.

The role of bradykinin in mediating ischemic brain edema in rats.

Background and Purpose: We investigated the hypothesis that bradykinin generation may induce ischemic brain edema in spontaneously hypertensive rats. Methods: Cerebral ischemia lasting 3 hours was produced by bilateral common carotid artery occlusion in 67 rats. After the ischemic period, the rats were reperfused. Cerebral water content and energy metabolites (adenosine triphosphate, lactate, and pyruvate), as well as plasma and tissue bradykinin, were measured. Additionally, using the same experimental paradigm, bradykinin synthesis inhibitors (aprotinin [n =7] and soybean trypsin inhibitor [n =7]) were administered immediately after ischemia induction to determine the relation of bradykinin generation to the progression of ischemic brain edema. Results: Cerebral water content increased during the 3‐hour ischemic period, peaked at 30 minutes of reperfusion, and declined thereafter. Bradykinin levels in plasma and tissue rose markedly 30 minutes after reperfusion and fell thereafter. The progressive loss of adenosine triphosphate was mirrored by the rise in lactate. In the treated groups, aprotinin and soybean trypsin inhibitor administration significantly attenuated cerebral edema (p < 0.01 and p <0.05, respectively). The treated groups also showed less lactate accumulation and more adenosine triphosphate preservation than did the controls. Conclusions: These results demonstrate that bradykinin levels in plasma and tissue corresponded to cerebral edema progression and that bradykinin suppression decreased edema formation. These novel findings indicate that bradykinin activation augments the progression of ischemic brain edema. (Stroke 1993;24:571‐576)

Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model

1. Rat bilateral common carotid artery occlusion (BCAO) was used as a chronic cerebral hypoperfusion model. We observed autoradiographically the long‐term changes in regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) after 2 days and 1, 4 and 8 weeks of BCAO and in controls. Regions evaluated included the cerebral cortex, white matter and basal ganglia. Pathological changes were also observed with Klüver–Barrera and haematoxylin–eosin staining.

Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial.

Background and Purpose— The antiplatelet agent sarpogrelate is a selective inhibitor of 5-hydroxytryptamine receptors. The purpose of this study was to compare the efficacy and safety of sarpogrelate with those of aspirin in Japanese ischemic stroke patients. Methods— In total, 1510 patients with recent cerebral infarction (1 week to 6 months after onset) were randomly assigned to receive either sarpogrelate (100 mg TID) or aspirin (81 mg/d). Mean follow-up period was 1.59 years. The primary efficacy end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event–related death) were selected as secondary end points. The aim of the primary efficacy analysis was to demonstrate the noninferiority of sarpogrelate with respect to aspirin, with the criterion that the upper limit of the 95% CI of the hazard ratio (sarpogrelate vs aspirin) for recurrence of cerebral infarction should not exceed 1.33. Results— Cerebral infarction recurred in 72 patients (6.09%/y) in the sarpogrelate group and in 58 (4.86%/y) in the aspirin group (hazard ratio=1.25; 95% CI, 0.89 to 1.77; P=0.19). A serious vascular event occurred in 90 (7.61%/y) and in 85 (7.12%/y) patients, respectively (hazard ratio=1.07; 95% CI, 0.80 to 1.44; P=0.65). The overall incidences of bleeding events were 89 (11.9%) and 131 (17.3%), respectively (P<0.01). Conclusions— Sarpogrelate was not noninferior to aspirin for prevention of recurrence of cerebral infarction. Bleeding events were significantly fewer with sarpogrelate than aspirin. The effect of aspirin in Japanese patients was similar to that in Western studies.

Brain eicosanoid levels in spontaneously hypertensive rats after ischemia with reperfusion: leukotriene C4 as a possible cause of cerebral edema.

The relation of brain eicosanoids to progression of cerebral edema was studied in stroke-resistant spontaneously hypertensive rats subjected to incomplete global brain ischemia induced by bilateral occlusion of the common carotid arteries. Thromboxane B2 and 6-keto prostaglandin F1 alpha levels were significantly elevated 5 minutes after reperfusion but returned to control levels by 30 minutes. In contrast, leukotriene C4 levels increased 2 hours after bilateral common carotid artery occlusion and peaked 30 minutes after reperfusion, with higher levels persisting until 60 minutes after reperfusion. Cerebral ischemia was accompanied by cerebral edema early after reperfusion. The edema correlated with increased leukotriene C4 levels. That the increased brain water content was causally related to an increase in leukotriene C4 was supported by results obtained following administration of the 5-lipoxygenase inhibitors ONO-LP-016 and AA-861. Both inhibitors suppressed the increased leukotriene C4 and brain water contents after reperfusion. Our results indicate that leukotriene C4 is closely associated with an induction of ischemic cerebral edema.

Increased intracellular Ca2+ concentration in the hippocampal CA1 area during global ischemia and reperfusion in the rat: a possible cause of delayed neuronal death

The crucial role of free cytosolic Ca2+ in ischemic neuronal damage has been studied in recent years. In the present report, changes in the intracellular Ca2+ concentration in the hippocampal CA1 area during transient global ischemia and reperfusion were measured using in vivo Ca2+ fluorometry with fura-2 in the four-vessel occlusion and reperfusion model in halothane-anesthetized rats. Marked changes were seen during 10-min global ischemia, with the intracellular Ca2+ concentration increasing gradually following application of the ischemic insult and rapidly about 2 min after the beginning of ischemia, and continuing to increase until reperfusion. On reperfusion, the intracellular Ca2+ concentration began to decrease and returned to the pre-ischemic level within 15 min. Induction of severe global ischemia was confirmed by the complete suppression of synaptic activity and the decrease in hippocampal temperature in the CA1 area. After seven days, CA1 pyramidal cell loss was observed histopathologically in the same rats which had undergone measurement of the intracellular Ca2+ concentration changes. In the present study, a temporal profile of the free cytosolic Ca2+ dynamics during ischemic and early post-ischemic period was determined in vivo. The results demonstrate that the intracellular Ca2+ concentration in the hippocampal CA1 area is transiently and markedly increased during a brief ischemia-inducing delayed neuronal death, implying that Ca2+ overload during cerebral ischemia is a possible cause of the delayed cell death of CA1 pyramidal neurons.

Antiplatelet Cilostazol Is Beneficial in Diabetic and/or Hypertensive Ischemic Stroke Patients

Background and Purpose: Although antiplatelets are known to be effective for secondary prevention of cerebral infarction, the number needed to treat is rather large and the effects in stroke patients with complications such as hypertension or diabetes are inadequately defined. This study was conducted to examine the effect of such complications on recurrence of cerebral infarction, and to assess the effect of cilostazol, an antiplatelet agent, in these high-risk subjects. Methods: A post hoc subgroup analysis of the already reported Cilostazol Stroke Prevention Study, which was a placebo-controlled double-blind trial, has been carried out to clarify the influence of various complications on recurrence in the placebo group and the effects of cilostazol in 1,095 patients with noncardioembolic ischemic cerebrovascular disease. Treatment continued for an average of 1.8 ± 1.3 years (maximum 4.8 years). Results: The recurrence rate of the diabetic stroke patients was significantly higher compared with the nondiabetics in the placebo group (9.4 vs. 4.7%/year, p = 0.01). Furthermore, our study showed that the relative risk reduction (RRR) for recurrence of infarction was 41.7% with cilostazol. This treatment provided a significant benefit in patients with lacunar infarction (RRR 43.4%, p = 0.04), with diabetes (RRR 64.4%, p = 0.008), or with hypertension (RRR 58.0%, p = 0.003). Conclusions: Diabetic patients are particularly at risk for recurrence of cerebral infarction. Cilostazol is useful for the prevention of the recurrence of vascular events in patients with lacunar infarction, and is probably effective in high-risk patients with diabetes and/or hypertension.

Effect of the Ca Antagonist Nilvadipine on Stroke Occurrence or Recurrence and Extension of Asymptomatic Cerebral Infarction in Hypertensive Patients with or without History of Stroke (PICA Study)

Background: We examined the effect of a Ca antagonist (nilvadipine) on the occurrence or recurrence of symptomatic stroke in hypertensive patients with MRI-defined asymptomatic cerebral infarction (ACI), periventricular hyperintensity (PVH), and deep and subcortical white matter hyperintensity (DSWMH), with or without a history of stroke, and evaluated the effect of long-term treatment on the lesions. Methods: Patients with hypertension and incidental ACI were divided into those with (group B, 235 patients) or without (group A, 181 patients) a history of symptomatic stroke, and were given nilvadipine 4–8 mg/day for 3 years. Primary evaluation points were occurrence of symptomatic ischemic stroke and development or extension of asymptomatic ischemic lesions. Results: Male sex, hyperuricemia, diabetes, maximum diameter of infarction and PVH severity were stronger risk factors for group B. Numbers of cerebral infarctions were 31 ± 28 (group A) and 42 ± 32 (group B) at enrollment (p < 0.001). Infarctions were larger and located more frequently on the internal capsule, putamen, thalamus and brainstem in group B. The severity of PVH and DSWMH paralleled the number of cerebral infarctions in both groups. Conclusion: The study design and status of asymptomatic ischemic brain lesions in hypertensive subjects at enrollment are presented.

Effect of long-term administration of ethyl eicosapentate (EPA-E) on local cerebral blood flow and glucose utilization in stroke-prone spontaneously hypertensive rats (SHRSP).

The objective of this study was to determine the effect of ethyl eicosopentate (EPA-E) on local cerebral blood flow (1-CBF) and local glucose utilization (1-CGU) in specific regions of the brain in stroke-prone spontaneously hypertensive rats (SHRSP). EPA-E (100 mg/kg body weight) or saline was orally administered to 8-week-old SHRSP. L-CBF and 1-CGU in the EPA-E-treated, saline-treated, and 8-week-old control rats were measured autoradiographically using 14C-iodoantipyrine and 14C-deoxyglucose (Sakuradas and Sokoloffs methods). The 1-CBF of the saline-treated group decreased significantly with age in all areas measured. EPA-E treatment alleviated the age-dependent decrease in 1-CBF in all areas, especially those in the basal ganglia. The 1-CGU of the saline-treated group did not change with age, however EPA-E treatment increased 1-CGU in all areas measured, though the changes were not significant. EPA-E ameliorated the decrease in cerebral blood flow and improved glucose metabolism in SHRSP suffering from severe hypertension. These results suggest that EPA-E may be useful in the prevention of stroke.