Neuroprotective Effect of an Antioxidant, Ebselen, in Patients with Delayed Neurological Deficits after Aneurysmal Subarachnoid Hemorrhage

Saito, Isamu; Asano, Takao; Sano, Keiji; Takakura, Kintomo; Abe, Hiroshi; Yoshimoto, Takashi; Kikuchi, Hiroe; Ohta, Tomio; Ishibashi, Shun

doi:10.1097/00006123-199802000-00038

Cited by 240 publications

(130 citation statements)

References 35 publications

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“…The remaining 24 trials were included in the analysis, including 8,552 patients (Macdonald et al, 2008;Asano et al, 1996;Chou et al, 2008;Gomis et al, 2010;Haley et al, 1993Haley et al, , 1997Hop et al, 2000;Kassell et al, 1996;Ohman and Heiskanen, 1988;Petruk et al, 1988;Pickard et al, 1989;Saito et al, 1998;Shaw et al, 2000;Shibuya et al, 1992;Siironen et al, 2003;Juvela et al, 2005;Springborg et al, 2007;Suzuki et al, 1989;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Westermaier et al, 2010;Wong et al, 2010Wong et al, , 2011. A total of 4,818 patients were randomized to pharmaceutical treatment, and 3,734 patients to placebo.…”

Section: Resultsmentioning

confidence: 99%

“…For blinding, risk of bias was low in 20 studies (Macdonald et al, 2008;Asano et al, 1996;Gomis et al, 2010;Haley et al, 1993Haley et al, , 1997Hop et al, 2000;Kassell et al, 1996;Petruk et al, 1988;Pickard et al, 1989;Shaw et al, 2000;Shibuya et al, 1992;Siironen et al, 2003;Springborg et al, 2007;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Westermaier et al, 2010;Wong et al, 2010), and unclear in four studies (Chou et al, 2008;Ohman and Heiskanen, 1988;Saito et al, 1998;Suzuki et al, 1989). High risk of bias was not observed in any of the studies.…”

Section: Risk Of Bias Assessmentsmentioning

confidence: 95%

“…For allocation concealment, risk of bias was low in 13 (Macdonald et al, 2008;Asano et al, 1996;Haley et al, 1993;Hop et al, 2000;Petruk et al, 1988;Pickard et al, 1989;Shaw et al, 2000;Shibuya et al, 1992;Springborg et al, 2007;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Wong et al, 2010) and unclear in 11 studies (Chou et al, 2008;Gomis et al, 2010;Haley et al, 1997;Kassell et al, 1996;Ohman and Heiskanen, 1988;Saito et al, 1998;Siironen et al, 2003;Suzuki et al, 1989;Westermaier et al, 2010) ( Table 1). For blinding, risk of bias was low in 20 studies (Macdonald et al, 2008;Asano et al, 1996;Gomis et al, 2010;Haley et al, 1993Haley et al, , 1997Hop et al, 2000;Kassell et al, 1996;Petruk et al, 1988;Pickard et al, 1989;Shaw et al, 2000;Shibuya et al, 1992;Siironen et al, 2003;Springborg et al, 2007;Tseng et al, 2009;van den Bergh et al, 2005van den Bergh et al, , 2006Westermaier et al, 2010;…”

Section: Risk Of Bias Assessmentsmentioning

confidence: 99%

“…Heterogeneity between the trials was significant in the cerebral infarction analysis (I 2 = 45% and P = 0.04), but not in the poor outcome analysis (I 2 = 0% and P = 0.62). In the sensitivity analysis that only included studies with an outcome assessment 3 months after SAH, 16 studies were included with 7,530 patients (Macdonald et al, 2008;Asano et al, 1996;Haley et al, 1993Haley et al, , 1997Kassell et al, 1996;Ohman and Heiskanen, 1988;Petruk et al, 1988;Pickard et al, 1989;Saito et al, 1998;Shaw et al, 2000;Siironen et al, 2003;Suzuki et al, 1989;van den Bergh et al, 2005van den Bergh et al, , 2006. The pooled RR for cerebral infarction was 0.87 (95% CI: 0.78 to 0.98) and for poor outcome 0.93 (95% CI: 0.86 to 1.00) (figures not shown).…”

Section: Sensitivity Analysesmentioning

confidence: 99%

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Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

Vergouwen

Etminan

Ilodigwe

et al. 2011

J Cereb Blood Flow Metab

128

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Despite an undisputed association between vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH), there is debate if this association implies causality. It has been suggested that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies. To further investigate the relationship between infarction and outcome, we performed a systematic review and meta-analysis of all randomized, double-blind, placebo-controlled trials that studied the efficacy of pharmaceutical preventive strategies in SAH patients, and had both cerebral infarction and clinical outcome as outcome events. Effect sizes were expressed in (pooled) risk ratio (RR) estimates with corresponding 95% confidence intervals (CIs). Sensitivity analyses were performed for studies with a low risk of bias and for those who reported outcome at 3 months after SAH. Twenty-four studies including 8,552 patients were included. Pharmaceutical treatments decreased the incidence of both cerebral infarction (RR: 0.83; 95% CI: 0.74 to 0.93) and of poor functional outcome (RR: 0.92; 95% CI: 0.86 to 0.98). The sensitivity analyses did not change the results essentially. These data suggest that the previously observed association between cerebral infarction and functional outcome implies causality, and that cerebral infarction is a better outcome measure than vasospasm in clinical trials and observational studies.

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Section: Resultsmentioning

confidence: 99%

Section: Risk Of Bias Assessmentsmentioning

confidence: 95%

Section: Risk Of Bias Assessmentsmentioning

confidence: 99%

Section: Sensitivity Analysesmentioning

confidence: 99%

See 2 more Smart Citations

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

Vergouwen

Etminan

Ilodigwe

et al. 2011

J Cereb Blood Flow Metab

128

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“…Ebselen also mitigates the increase of serum ALT observed in alcohol-induced liver injury (Kono et al 2001). Ebselen possesses glutathione peroxidase-like action (Parnham et al 1988) and has been shown to be a potent neuroprotective agent during both stroke and subarachnoid haemorrhage in man (Saito et al 1998) and in animal models of neurodegenerative diseases (Dawson et al 1995;Takasago et al 1997). Membrane lipid peroxidation can induce damage, including transition in permeability and release of apoptotic factors that lead to cell death (Mattson 1998).…”

Section: Discussionmentioning

confidence: 99%

Ebselen Protects against the Reduction in Levels of Drug‐Metabolizing Enzymes in Livers of Rats with Deoxycholic Acid‐Induced Liver Injury

Tanaka

Takezawa

Kumai

et al. 2002

Pharmacology & Toxicology

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Ebselen is a seleno-organic compound that inhibits oxidative stress by lipid peroxidation through a glutathione peroxidase-like activity. We studied the effect of ebselen on the expression of hepatic drug-metabolizing enzymes in rats with deoxycholic acid-induced liver injury. Hydrophobic bile acids, such as deoxycholic acid, are known to cause cholestatic liver injury, and it was reported that expression of hepatic cytochrome P-450 (CYP) was reduced by deoxycholic acid administration in rats. Hydrophobic bile acids induce lipid peroxidation in the liver, and this may be one mechanism of the development of liver injury. In the present study, we investigated the effect of ebselen (30 mg/kg/day for 10 days) on rats ingesting deoxycholic acid (1% of diet for 10 days). Deoxycholic acid decreased levels of CYP1A1, 2B1, 2E1 and 3A2 to 34, 58, 62 and 37% of control values, respectively, and increased serum alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activities to 1.8 and 8.6 times the levels of controls, respectively. Administration of ebselen with deoxycholic acid prevented the decreases in levels of CYP1A1 and 3A2 (86 and 65% of control, respectively) and the increases in serum ALP and ALT activities (1.4 and 1.9 times of control, respectively) caused by deoxycholic acid. These results indicate that ebselen may have a protective effect against hydrophobic bile acid-induced liver injury.

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Antioxidant Therapy in Neurologic Disease

Delanty¹,

Dichter²

2000

Arch Neurol

120

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Free radical or oxidative injury may be a fundamental mechanism underlying a number of human neurologic diseases. Therapy using free radical scavengers (antioxidants) has the potential to prevent, delay, or ameliorate many neurologic disorders. However, the biochemistry of oxidative pathobiology is complex, and optimum antioxidant therapeutic options may vary and need to be tailored to individual diseases. In vitro and animal model studies support the potential beneficial role of various antioxidant compounds in neurologic disease. However, the results of clinical trials using various antioxidants, including vitamin E, tirilazad, N-acetylcysteine, and ebselen, have been mixed. Potential reasons for these mixed results include lack of pretrial dose-finding studies and failure to appreciate and characterize the individual unique oxidative processes occurring in different diseases. Moreover, therapy with antioxidants may need to be given early in chronic insidious neurologic disorders to achieve an appreciable clinical benefit. Predisease screening and intervention in at-risk individuals may also need to be considered in the near future.

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Neuroprotective Effect of an Antioxidant, Ebselen, in Patients with Delayed Neurological Deficits after Aneurysmal Subarachnoid Hemorrhage

Abstract: Ebselen reduced brain damage in patients with delayed neurological deficits after subarachnoid hemorrhage and may be a promising neuroprotective agent.

Cited by 240 publications

References 35 publications

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage

Ebselen Protects against the Reduction in Levels of Drug‐Metabolizing Enzymes in Livers of Rats with Deoxycholic Acid‐Induced Liver Injury

Antioxidant Therapy in Neurologic Disease

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