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Kenneth Rockwood - One of the best experts on this subject based on the ideXlab platform.
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Size of the treatment effect on cognition of Cholinesterase Inhibition in Alzheimer’s disease
Journal of neurology neurosurgery and psychiatry, 2004Co-Authors: Kenneth RockwoodAbstract:Background: Six Cholinesterase inhibitors (ChEIs) have been tested in people with Alzheimer’s disease, using methods currently required for regulatory approval. The clinical importance of their treatment effects is controversial. Objective: To determine whether Cholinesterase Inhibition produces treatment effects in Alzheimer’s disease that are large enough to be clinically detectable. Methods: Overview analysis of published trials of ChEIs in which the Alzheimer’s Disease Assessment Scale—Cognitive Subscale (ADAS-Cog) and a global clinical measure were primary outcomes. Two quantitative summary measures of the treatment effect (Cohen’s d and the standardised response mean (SRM)) were calculated and presented as funnel plots. Observed cases analyses and intention to treat (ITT) with the last observation carried forward (LOCF) analyses were compared. Results: The median Cohen’s d effect sizes (ES) using ITT samples with LOCF for the ADAS-Cog were: low dose of a ChEI (n = 8 studies) median ES = 0.15, range = 0.03–0.22; medium dose (n = 13) median ES = 0.23, range = 0.12–0.29; high dose (n = 9) median ES = 0.28, range = 0.01–0.31. In general, the ES were larger when calculated as SRMs (for example, high dose ChEI studies, median SRM = 0.47; range = 0.30–0.63) and highest in the observed cases analyses (for example, high dose median SRM = 0.56, range = 0.35–0.78). Global clinical scales produced similar estimates of ES (for example, high dose ChEI, ITT/LOCF median Cohen’s d = 0.29, range = 0.20–0.47). Conclusions: ChEIs produce small-moderate effect sizes in clinical trials which are reproducible and demonstrate a dose response. Better descriptions of the patterns of treatment response are needed to guide individual patient decisions about the effectiveness of treatment, but group effects are evident and appear large enough to be clinically detectable.
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size of the treatment effect on cognition of Cholinesterase Inhibition in alzheimer s disease
Journal of Neurology Neurosurgery and Psychiatry, 2004Co-Authors: Kenneth RockwoodAbstract:Background: Six Cholinesterase inhibitors (ChEIs) have been tested in people with Alzheimer’s disease, using methods currently required for regulatory approval. The clinical importance of their treatment effects is controversial. Objective: To determine whether Cholinesterase Inhibition produces treatment effects in Alzheimer’s disease that are large enough to be clinically detectable. Methods: Overview analysis of published trials of ChEIs in which the Alzheimer’s Disease Assessment Scale—Cognitive Subscale (ADAS-Cog) and a global clinical measure were primary outcomes. Two quantitative summary measures of the treatment effect (Cohen’s d and the standardised response mean (SRM)) were calculated and presented as funnel plots. Observed cases analyses and intention to treat (ITT) with the last observation carried forward (LOCF) analyses were compared. Results: The median Cohen’s d effect sizes (ES) using ITT samples with LOCF for the ADAS-Cog were: low dose of a ChEI (n = 8 studies) median ES = 0.15, range = 0.03–0.22; medium dose (n = 13) median ES = 0.23, range = 0.12–0.29; high dose (n = 9) median ES = 0.28, range = 0.01–0.31. In general, the ES were larger when calculated as SRMs (for example, high dose ChEI studies, median SRM = 0.47; range = 0.30–0.63) and highest in the observed cases analyses (for example, high dose median SRM = 0.56, range = 0.35–0.78). Global clinical scales produced similar estimates of ES (for example, high dose ChEI, ITT/LOCF median Cohen’s d = 0.29, range = 0.20–0.47). Conclusions: ChEIs produce small-moderate effect sizes in clinical trials which are reproducible and demonstrate a dose response. Better descriptions of the patterns of treatment response are needed to guide individual patient decisions about the effectiveness of treatment, but group effects are evident and appear large enough to be clinically detectable.
Daland R. Juberg - One of the best experts on this subject based on the ideXlab platform.
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Cholinesterase Inhibition and toxicokinetics in immature and adult rats after acute or repeated exposures to chlorpyrifos or chlorpyrifos oxon
Regulatory Toxicology and Pharmacology, 2012Co-Authors: Mary Sue Marty, Amanda K. Andrus, M. P. Bell, Julie K. Passage, Adam W. Perala, Kathy A. Brzak, Michael J. Bartels, Melissa J. Beck, Daland R. JubergAbstract:Abstract The effect of age or dose regimen on Cholinesterase Inhibition (ChEI) from chlorpyrifos (CPF) or CPF–oxon (CPFO) was studied in Crl:CD(SD) rats. Rats were exposed to CPF by gavage in corn oil, rat milk (pups), or in the diet (adults) or to CPFO by gavage in corn oil. Blood CPF/CPFO levels were measured. With acute exposure, ChEI NOELs were 2 mg/kg CPF for brain and 0.5 mg/kg CPF for red blood cells (RBCs) in both age groups. In pups, ChEI and blood CPF levels were similar using either milk or corn oil vehicles. Compared to gavage, adults given dietary CPF (12 h exposure) had greater RBC ChEI, but lower brain ChEI at corresponding CPF doses, indicating an effect of dose rate. With repeated CPF exposures, ChEI NOELs were the same across ages (0.5 and 0.1 mg/kg/day for brain and RBCs, respectively). With CPFO dosing, the ChEI NOELs were 0.1 mg/kg (acute) and 0.01 mg/kg/day (repeated doses) for RBCs with no ChEI in brain at CPFO doses up to 0.5 (pup) or 10 mg/kg (adult) for acute dosing or 0.5 mg/kg/day for both ages with repeat dosing. Thus, there were no age-dependent differences in CPF ChEI via acute or repeated exposures. Pups had less ChEI than adults at comparable blood CPF levels. Oral CPFO resulted in substantial RBC ChEI, but no brain ChEI, indicating no CPFO systemic bioavailability to peripheral tissues.
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Cholinesterase Inhibition and Toxicokinetics in Immature and Adult Rats After Acute or Repeated Exposures to Chlorpyrifos or Chlorpyrifos–oxon
Regulatory toxicology and pharmacology : RTP, 2012Co-Authors: Mary Sue Marty, Amanda K. Andrus, M. P. Bell, Julie K. Passage, Adam W. Perala, Kathy A. Brzak, Michael J. Bartels, Melissa J. Beck, Daland R. JubergAbstract:Abstract The effect of age or dose regimen on Cholinesterase Inhibition (ChEI) from chlorpyrifos (CPF) or CPF–oxon (CPFO) was studied in Crl:CD(SD) rats. Rats were exposed to CPF by gavage in corn oil, rat milk (pups), or in the diet (adults) or to CPFO by gavage in corn oil. Blood CPF/CPFO levels were measured. With acute exposure, ChEI NOELs were 2 mg/kg CPF for brain and 0.5 mg/kg CPF for red blood cells (RBCs) in both age groups. In pups, ChEI and blood CPF levels were similar using either milk or corn oil vehicles. Compared to gavage, adults given dietary CPF (12 h exposure) had greater RBC ChEI, but lower brain ChEI at corresponding CPF doses, indicating an effect of dose rate. With repeated CPF exposures, ChEI NOELs were the same across ages (0.5 and 0.1 mg/kg/day for brain and RBCs, respectively). With CPFO dosing, the ChEI NOELs were 0.1 mg/kg (acute) and 0.01 mg/kg/day (repeated doses) for RBCs with no ChEI in brain at CPFO doses up to 0.5 (pup) or 10 mg/kg (adult) for acute dosing or 0.5 mg/kg/day for both ages with repeat dosing. Thus, there were no age-dependent differences in CPF ChEI via acute or repeated exposures. Pups had less ChEI than adults at comparable blood CPF levels. Oral CPFO resulted in substantial RBC ChEI, but no brain ChEI, indicating no CPFO systemic bioavailability to peripheral tissues.
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AcetylCholinesterase Inhibition dose-response modeling for chlorpyrifos and chlorpyrifos-oxon.
Regulatory toxicology and pharmacology : RTP, 2012Co-Authors: Richard Reiss, Barbara H. Neal, James C. Lamb, Daland R. JubergAbstract:Abstract This paper evaluates new data for Cholinesterase Inhibition with chlorpyrifos (CPF). Marty et al. (2012) recently conducted a CPF Cholinesterase Inhibition study in rats that included testing of males and females, dosing by gavage or diet, administration in corn oil or milk, and with pups and adults. Additionally, the study included Cholinesterase Inhibition testing for CPF-oxon, the active moiety that inhibits Cholinesterase. The study included 5–6 dose groups with eight animals/sex/group for most of the tests. This paper provides a benchmark dose (BMD) analysis of the data from Marty et al. (2012) , including a BMD meta-analysis that includes CPF Cholinesterase Inhibition data from different assays within the Marty et al. (2012) study and, in one case, from another study. From the meta-analysis, the recommended BMD 10 s, based on brain acetylCholinesterase Inhibition, are 1.7 mg/kg/day (BMDL 10 = 1.3 mg/kg/day) for acute doses to children and adults, and 0.67 mg/kg/day (BMDL 10 = 0.53 mg/kg/day) for repeat doses to children and adults. At the dose levels considered in this analysis, there was no evidence of a difference in responses between males and females, corn oil versus milk administration, or pups versus adults. The data on pups versus adults show that an extra safety factor to protect the young is not needed for CPF. CPF data from the literature suggest that brain Cholinesterase Inhibition is the most appropriate metric for Cholinesterase Inhibition risk assessment.
Mary Sue Marty - One of the best experts on this subject based on the ideXlab platform.
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Cholinesterase Inhibition and toxicokinetics in immature and adult rats after acute or repeated exposures to chlorpyrifos or chlorpyrifos oxon
Regulatory Toxicology and Pharmacology, 2012Co-Authors: Mary Sue Marty, Amanda K. Andrus, M. P. Bell, Julie K. Passage, Adam W. Perala, Kathy A. Brzak, Michael J. Bartels, Melissa J. Beck, Daland R. JubergAbstract:Abstract The effect of age or dose regimen on Cholinesterase Inhibition (ChEI) from chlorpyrifos (CPF) or CPF–oxon (CPFO) was studied in Crl:CD(SD) rats. Rats were exposed to CPF by gavage in corn oil, rat milk (pups), or in the diet (adults) or to CPFO by gavage in corn oil. Blood CPF/CPFO levels were measured. With acute exposure, ChEI NOELs were 2 mg/kg CPF for brain and 0.5 mg/kg CPF for red blood cells (RBCs) in both age groups. In pups, ChEI and blood CPF levels were similar using either milk or corn oil vehicles. Compared to gavage, adults given dietary CPF (12 h exposure) had greater RBC ChEI, but lower brain ChEI at corresponding CPF doses, indicating an effect of dose rate. With repeated CPF exposures, ChEI NOELs were the same across ages (0.5 and 0.1 mg/kg/day for brain and RBCs, respectively). With CPFO dosing, the ChEI NOELs were 0.1 mg/kg (acute) and 0.01 mg/kg/day (repeated doses) for RBCs with no ChEI in brain at CPFO doses up to 0.5 (pup) or 10 mg/kg (adult) for acute dosing or 0.5 mg/kg/day for both ages with repeat dosing. Thus, there were no age-dependent differences in CPF ChEI via acute or repeated exposures. Pups had less ChEI than adults at comparable blood CPF levels. Oral CPFO resulted in substantial RBC ChEI, but no brain ChEI, indicating no CPFO systemic bioavailability to peripheral tissues.
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Cholinesterase Inhibition and Toxicokinetics in Immature and Adult Rats After Acute or Repeated Exposures to Chlorpyrifos or Chlorpyrifos–oxon
Regulatory toxicology and pharmacology : RTP, 2012Co-Authors: Mary Sue Marty, Amanda K. Andrus, M. P. Bell, Julie K. Passage, Adam W. Perala, Kathy A. Brzak, Michael J. Bartels, Melissa J. Beck, Daland R. JubergAbstract:Abstract The effect of age or dose regimen on Cholinesterase Inhibition (ChEI) from chlorpyrifos (CPF) or CPF–oxon (CPFO) was studied in Crl:CD(SD) rats. Rats were exposed to CPF by gavage in corn oil, rat milk (pups), or in the diet (adults) or to CPFO by gavage in corn oil. Blood CPF/CPFO levels were measured. With acute exposure, ChEI NOELs were 2 mg/kg CPF for brain and 0.5 mg/kg CPF for red blood cells (RBCs) in both age groups. In pups, ChEI and blood CPF levels were similar using either milk or corn oil vehicles. Compared to gavage, adults given dietary CPF (12 h exposure) had greater RBC ChEI, but lower brain ChEI at corresponding CPF doses, indicating an effect of dose rate. With repeated CPF exposures, ChEI NOELs were the same across ages (0.5 and 0.1 mg/kg/day for brain and RBCs, respectively). With CPFO dosing, the ChEI NOELs were 0.1 mg/kg (acute) and 0.01 mg/kg/day (repeated doses) for RBCs with no ChEI in brain at CPFO doses up to 0.5 (pup) or 10 mg/kg (adult) for acute dosing or 0.5 mg/kg/day for both ages with repeat dosing. Thus, there were no age-dependent differences in CPF ChEI via acute or repeated exposures. Pups had less ChEI than adults at comparable blood CPF levels. Oral CPFO resulted in substantial RBC ChEI, but no brain ChEI, indicating no CPFO systemic bioavailability to peripheral tissues.
A. Hamid A. Hadi - One of the best experts on this subject based on the ideXlab platform.
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Synthesis, Characterization, X-ray Crystallography, Acetyl Cholinesterase Inhibition and Antioxidant Activities of Some Novel Ketone Derivatives of Gallic Hydrazide-Derived Schiff Bases
Molecules, 2012Co-Authors: Nura Suleiman Gwaram, Mahmood Ameen Abdulla, Michael J. C. Buckle, Sri Devi Sukumaran, Lip Yong Chung, Rozana Othman, Abeer A. Alhadi, Wageeh A. Yehye, A. Hamid A. HadiAbstract:Alzheimer’s disease (AD) is the most common form of dementia among older people and the pathogenesis of this disease is associated with oxidative stress. AcetylCholinesterase inhibitors with antioxidant activities are considered potential treatments for AD. Some novel ketone derivatives of gallic hydrazide-derived Schiff bases were synthesized and examined for their antioxidant activities and in vitro and in silico acetyl Cholinesterase Inhibition. The compounds were characterized using spectroscopy and X-ray crystallography. The ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays revealed that all the compounds have strong antioxidant activities. N-(1-(5-bromo-2-hydroxyphenyl)-ethylidene)-3,4,5-trihydroxybenzohydrazide (2) was the most potent inhibitor of human acetyl Cholinesterase, giving an Inhibition rate of 77% at 100 μM. Molecular docking simulation of the ligand-enzyme complex suggested that the ligand may be positioned in the enzyme’s active-site gorge, interacting with residues in the peripheral anionic subsite (PAS) and acyl binding pocket (ABP). The current work warrants further preclinical studies to assess the potential for these novel compounds for the treatment of AD.
Rafal Janik - One of the best experts on this subject based on the ideXlab platform.
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attenuation of functional hyperemia to visual stimulation in mild alzheimer s disease and its sensitivity to Cholinesterase Inhibition
Biochimica et Biophysica Acta, 2016Co-Authors: Rafal Janik, Lynsie A M Thomason, Simone Chaudhary, Adrienne Dorr, Amy Scouten, Graeme Schwindt, Mario MasellisAbstract:Abstract Despite the growing recognition of the significance of cerebrovascular impairment in the etiology and progression of Alzheimer's disease (AD), the early stage brain vascular dysfunction and its sensitivity to pharmacological interventions is still not fully characterized. Due to the early and aggressive treatment of probable AD with Cholinesterase inhibitors (ChEI), which in and of themselves have direct effects on brain vasculature, the vast majority of hemodynamic measurements in early AD subjects reported hitherto have consequently been made only after the start of treatment, complicating the disentanglement of disease- vs. treatment-related effects on the cerebral vasculature. To address this gap, we used pseudo continuous arterial spin labeling MRI to measure resting perfusion and visual stimulation elicited changes in cerebral blood flow (CBF) and blood oxygenation dependent (BOLD) fMRI signal in a cohort of mild AD patients immediately prior to, 6 months post, and 12 months post commencement of open label Cholinesterase inhibitor treatment. Although patients exhibited no gray matter atrophy prior to treatment and their resting perfusion was not distinguishable from that in age, education and gender-matched controls, the patients' visual stimulation-elicited changes in BOLD fMRI and blood flow were decreased by 10 ± 4% (BOLD) and 23 ± 2% (CBF), relative to those in controls. Induction of Cholinesterase Inhibition treatment was associated with a further, 7 ± 2% reduction in patients' CBF response to visual stimulation, but it stabilized, at this new lower level, over the follow-up period. Likewise, MMSE scores remained stable during the treatment; furthermore, higher MMSE scores were associated with higher perfusion responses to visual stimulation. This study represents the initial step in disentangling the effects of AD pathology from those of the first line treatment with Cholinesterase inhibitors on cerebral hemodynamics and supports the use of arterial spin labeling MRI for quantitative evaluation of the brain vascular function in mild Alzheimer's disease. The findings provide evidence of a pronounced deficit in the visual cortex hyperemia despite the relative sparing of visual function in early stage AD, its reduction with ChEI treatment induction, and its stabilization in the first year of Cholinesterase Inhibition treatment. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
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Hemodynamic effects of Cholinesterase Inhibition in mild Alzheimer's disease.
Journal of magnetic resonance imaging : JMRI, 2012Co-Authors: Simone Chaudhary, Rafal Janik, Amy Scouten, Graeme Schwindt, Wayne Lee, John G. Sled, Sandra E. Black, Bojana StefanovicAbstract:Purpose To evaluate the spatiotemporal progression of perfusion changes in early stages of Alzheimer's disease (AD), we imaged the perfusion response to pharmacological treatment in a group of mild AD patients and contrasted it to the perfusion of age-, sex-, and education-matched healthy volunteers over the same time interval. Materials and Methods We used pseudo continuous arterial spin labeling (PCASL) MRI for quantitative three-dimensional mapping of perfusion immediately before and 6 months after Cholinesterase inhibitor treatment. Results Before treatment, patients were found hypoperfused relative to their healthy counterparts in the gray matter of lateral temporal lobe, posterior cingulate, and anterior cingulate as well as in the white matter of the posterior cingulate. Most of the cortical regions investigated and the white matter of posterior cingulate and prefrontal regions showed treatment-elicited increases in perfusion, which were not secondary to changes in regional tissue volume nor were they associated with improvement in either MMSE or ADAS-Cog scores, although lack of deterioration suggested a cognitive benefit. Conclusion This study provides a hemodynamic profile of mild AD and sheds light on the perfusion changes related to prolonged Cholinesterase Inhibition in this early disease stage. J. Magn. Reson. Imaging 2013;38:26–35. © 2013 Wiley Periodicals, Inc.