Metal ion chelation in neurodegenerative disorders

Angel, Itzchak; Bar, Adina; Horovitz, Tammy; Taler, Galia; Krakovsky, Michael; Resnitsky, Dalia; Rosenberg, G; Striem, S.; Friedman, Jonathan E.; Kozak, Alex

doi:10.1002/ddr.10083

Cited by 44 publications

(54 citation statements)

References 62 publications

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“…13 The membrane-activated, zinc-specific chelating agent DP-b99 was postulated to offer neuroprotective or neurorestorative effects in experimental stroke. [13][14][15][16] DP-b99 seemed well tolerated by patients with acute stroke, and a phase IIb trial reported better outcomes among DP-b99-treated patients than a control group on a secondary outcome measure. 17 Post hoc subgroup analysis suggested that the greatest intergroup difference was present among patients with stroke of moderate severity (National Institutes of Health Stroke Scale [NIHSS] 10 to 16) who had features suggestive of cortical damage.…”

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Results of Membrane-activated Chelator Stroke Intervention Randomized Trial of DP-b99 in Acute Ischemic Stroke

Lees

Bornstein

Diener

et al. 2013

Stroke

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Background and Purpose-DP-b99, a lipophilic moderate-affinity chelator of zinc, was postulated to improve recovery after acute ischemic stroke. We evaluated the safety and therapeutic effects of DP-b99 in patients with acute hemispheric ischemic stroke. Methods-The Membrane-Activated Chelator Stroke Intervention trial was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial of intravenous DP-b99 administered for 4 consecutive days (NCT00893867). Acute ischemic stroke patients within 9 hours of onset, but untreated by alteplase, with a baseline National Institutes of Health Stroke Scale score of 10 to 16, and evidence of language dysfunction, visual field defect, and neglect were eligible. The primary efficacy analysis compared distributions of functional status measured by modified Rankin score in the intentto-treat population of patients with any post-treatment outcome, adjusted for initial severity. Functional and neurological recovery were secondary measures. Home time was an exploratory end point. Results-Enrollment terminated at n=446 after the planned interim analysis determined futility; follow-up continued. Final modified Rankin score distributions were equal between DP-b99 and placebo-treated groups (P=0.10; P adj adjusted for baseline age and National Institutes of Health Stroke Scale=0.21). Fewer patients recovered to modified Rankin score ≤1 in the DP-b99-treated group (45/218; 20.6%) than after placebo (63/219; 28.8%) (P=0.05; P adj =0.10). Similarly, fewer patients attained National Institutes of Health Stroke Scale ≤1 after DP-b99 (42/

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confidence: 99%

Results of Membrane-activated Chelator Stroke Intervention Randomized Trial of DP-b99 in Acute Ischemic Stroke

Lees

Bornstein

Diener

et al. 2013

Stroke

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“…In the present study, which included only patients with cortical involvement and thus, those most likely with large hemispheric infarcts, the dose used (1 mg/kg per day) was 2 to 3 orders of magnitude higher than that used in preclinical in vivo studies. 7 Previous exposure of healthy volunteers and stroke patients to repeated DP-b99 administrations of 1 mg/kg per day have shown this dose to be safe. 10,11 In an earlier small-scale study of this dose administered to acute stroke patients for 2 consecutive days (with a treatment window of 12 hours), a larger decrease from baseline on the National Institutes of Heath Stroke Scale (NIHSS) was observed with DP-b99 compared with placebo after a 30-day follow-up.…”

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“…6 DP-b99 is a membrane-activated lipophilic chelator of divalent metal ions that is designed to chelate these ions only in the vicinity of membranes and when their concentrations exceed physiologic levels, thus affecting the function of proteins that require these ions for their activation. 7 In cellular systems, DP-b99 has been shown to atten-uate detrimental zinc-dependent membrane-associated processes, such as calpain activation and tumor necrosis factor-␣-induced activation of matrix metalloproteinase-9. 7 In rodent models of cerebral ischemia, DP-b99 therapy reduced infarct volume and neuron-specific enolase release and increased the survival rate.…”

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“…7 In cellular systems, DP-b99 has been shown to atten-uate detrimental zinc-dependent membrane-associated processes, such as calpain activation and tumor necrosis factor-␣-induced activation of matrix metalloproteinase-9. 7 In rodent models of cerebral ischemia, DP-b99 therapy reduced infarct volume and neuron-specific enolase release and increased the survival rate. 7,8 Two of the problems hindering the extension of findings from animal stroke models to the clinic are the immense differences between laboratory animals and patients in terms of absolute infarct size and the much longer treatment window commonly called for in the clinical setting.…”

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“…7 In rodent models of cerebral ischemia, DP-b99 therapy reduced infarct volume and neuron-specific enolase release and increased the survival rate. 7,8 Two of the problems hindering the extension of findings from animal stroke models to the clinic are the immense differences between laboratory animals and patients in terms of absolute infarct size and the much longer treatment window commonly called for in the clinical setting. 9 When moving from bench to bedside, it is therefore reasonable to try and shorten the time needed to achieve adequate tissue drug levels-and overcome the longer diffusion distances in the poorly perfused human penumbra-by increasing the neuroprotectant's serum levels beyond those used in the laboratory setting (safety permitting), so as to create a gradient that will promptly and effectively drive the drug into the target tissue.…”

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DP-b99, a Membrane-Activated Metal Ion Chelator, as Neuroprotective Therapy in Ischemic Stroke

Diener

Schneider

Lampl

et al. 2008

Stroke

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Background and Purpose-DP-b99 is a chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke. We present the results of a multicenter, double-blind, placebo-controlled, randomized trial to assess the safety and potential protective effects of DP-b99 in acute ischemic stroke. Methods-One hundred and fifty stroke patients with signs of cortical involvement and a National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20 received a 4-day course of intravenous 1 mg/kg per day DP-b99 or placebo within 1 to 9 hours of stroke onset. Treatment with recombinant tissue plasminogen activator was not allowed. Results-No major differences in mortality rate, causes of death, adverse events, safety laboratory tests, and ECG parameters were found between the 2 groups. The baseline NIHSS score of the 72 DP-b99 -and 75 placebo-treated patients in the intent-to-treat cohort was (meanϮSD) 12.2Ϯ4.0 and 12.6Ϯ3.3, respectively; the time to needle (meanϮSD) was 6:36Ϯ1:47 and 6:28Ϯ1:33 hours, respectively; and the age (meanϮSD) was 73.3Ϯ9.9 and 72.0Ϯ9.6 years, respectively. The 90-day median change from baseline (the primary end point) was Ϫ6.0 and Ϫ5.0 NIHSS points in the DP-b99 and placebo groups, respectively (nonsignificant). At 90 days, there was a significantly better outcome in the DP-b99 group compared with the placebo group (modified Rankin scale score of 0, 1, or same as prestroke): 30.6% and 16.0%, respectively (Pϭ0.05). The recovery rate was unaffected by the time to needle. Further analyses indicated that the 90-day median change from baseline in patients with an entry NIHSS score of 10 to 16 was 8.0 and 5.0 points in the DP-b99 and placebo groups, respectively (Pϭ0.03). Conclusions-In this small-scale study, the primary end point of change in NIHSS score from baseline to 90 days was not met. However, secondary end points demonstrated a significantly improved 90-day recovery rate with treatment with DP-b99 when compared with placebo. In addition, in patients with baseline NIHSS scores of 10 to 16, a significant post hoc change in NIHSS score from baseline to day 90 was observed. No major safety problems were identified. These findings need to be confirmed with a larger prospective study of strokes involving the cortex. (Stroke. 2008; 39:1774-1778.)

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Neuroprotective Drugs

Murozono

2015

Neuroanesthesia and Cerebrospinal Protection

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Metal ion chelation in neurodegenerative disorders

Cited by 44 publications

References 62 publications

Results of Membrane-activated Chelator Stroke Intervention Randomized Trial of DP-b99 in Acute Ischemic Stroke

Results of Membrane-activated Chelator Stroke Intervention Randomized Trial of DP-b99 in Acute Ischemic Stroke

DP-b99, a Membrane-Activated Metal Ion Chelator, as Neuroprotective Therapy in Ischemic Stroke

Neuroprotective Drugs

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