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Stevioside, a constituent of Stevia rebaudiana, is commonly used as a non-caloric sugar substitute in Japan. The genetic toxicities of stevioside and its aglycone, steviol, were examined with seven mutagenicity tests using bacteria (reverse mutation assay, forward mutation assay, umu test and rec assay), cultured mammalian cells (chromosomal aberration test and gene mutation assay) and mice (micronucleus test). Stevioside was not mutagenic in any of the assays examined. The aglycone, steviol, however, produced dose-related positive responses in some mutagenicity tests, i.e. the forward mutation assay using Salmonella typhimurium TM677, the chromosomal aberration test using Chinese hamster lung fibroblast cell line (CHL) and the gene mutation assay using CHL. Metabolic activation systems containing 9000 g supernatant fraction (S9) of liver homogenates prepared from polychlorinated biphenyl or phenobarbital plus 5,6-benzoflavone-pretreated rats were required for mutagenesis and clastogenesis. Steviol was weakly positive in the umu test using S.typhimurium TA1535/pSK1002 either with or without the metabolic activation system. Steviol, even in the presence of the S9 activation system, was negative in other assays, i.e. the reverse mutation assays using S.typhimurium TA97, TA98, TA100, TA102, TA104, TA1535, TA1537 and Escherichia coli WP2 uvrA/pKM101 and the rec-assay using Bacillus subtilis. Steviol was negative in the mouse micronucleus test. The genotoxic risk of steviol to humans is discussed.

Satisfactory results have not yet been obtained in therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome (APS). We therefore compared single antiplatelet therapy and a combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with APS. The subjects were 20 ischemic stroke patients with antiphospholipid antibody, 13 with primary antiphospholipid syndrome and 7 with SLE-related antiphospholipid syndrome. Diagnosis of APS was based on the 2006 Sydney criteria. Eligible patients were randomly assigned to either single antiplatelet therapy (aspirin 100 mg) or a combination of antiplatelet and anticoagulation therapy (target INR: 2.0-3.0; mean 2.4±0.3) for the secondary prevention of stroke according to a double-blind protocol. There was no significant difference between the two groups in age, gender, NIH Stroke Scale on admission, mRS at discharge, or rate of hypertension, diabetes mellitus, hyperlipidemia, or cardiac disease. We obtained Kaplan-Meier survival curves for each treatment. The primary outcome was the occurrence of stroke. The mean follow-up time was 3.9±2.0 years. The cumulative incidence of stroke in patients with single antiplatelet treatment was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy (log-rank test, p-value=0.026). The incidence of hemorrhagic complications was similar in the two groups. The recent APASS study did not show any difference in effectiveness for secondary prevention between single antiplatelet (aspirin) and single anticoagulant (warfarin) therapy. Our results indicate that combination therapy may be more effective in APS-related ischemic stroke.

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.

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