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Massoud Mahmoudian – One of the best experts on this subject based on the ideXlab platform.

  • The Effect of Noscapine on Oxygen-Glucose Deprivation on Primary Murine Cortical Neurons in High Glucose Condition.
    Iranian journal of pharmaceutical research : IJPR, 2016
    Co-Authors: Gelareh Vahabzadeh, Soltan Ahmed Ebrahimi, Nahid Rahbar-roshandel, Massoud Mahmoudian
    Abstract:

    In the present work we set out to investigate the neuroprotective effects of Noscapine (0.5-2 µM) in presence of D-glucose on primary murine foetal cortical neurons after oxygen-glucose deprivation/24 h. recovery. Cell viability, nitric oxide production and intracellular calcium ((ca(2+))i) levels were evaluated by MTT assay, the modified Griess method and Fura-2 respectively. 25 and 100 mM D-glucose could, in a concentration dependent manner, improve cell viability and decrease NO production and (ca(2+))i level in neuronal cells after ischemic insult. Moreover, pre-incubation of cells with Noscapine, noticeably enhanced protective effects of 25 and 100 mM D-glucose compared to similar conditions without Noscapine pre-treatment. In fact, Noscapine attenuated NO production in a dose-dependent fashion, after 30 minutes (min) OGD, during high-glucose (HG) condition in cortical neurons. Pretreatment with 2 μM Noscapine and 25 or 100 mM D-glucose, was shown to decrease the rise in (ca(2+))i induced by Sodium azide/glucose deprivation (chemical OGD) model. These effects were more pronounced than that of 25 or 100 mM D-glucose alone. The present study demonstrated that the neuroprotective effects of HG before an ischemic insult were augmented by pre-treatment with Noscapine. Our results also suggested that the neuroprotection offered by both HG and Noscapine involve attenuation of NO production and (ca(2+))i levels stimulated by the experimental ischischemia in cortical neurons.

  • Neuroprotective effect of Noscapine on cerebral oxygen–glucose deprivation injury
    Pharmacological reports : PR, 2014
    Co-Authors: Gelareh Vahabzadeh, Nahid Rahbar-roshandel, Soltan-ahmad Ebrahimi, Massoud Mahmoudian
    Abstract:

    The present study aims to investigate the effect of Noscapine (0.5-2.5 μM), an alkaloid from the opium poppy, on primary murine fetal cortical neurons exposed to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Cells were transferred to glucose-free DMEM and were exposed to hypoxia in a small anaerobic chamber. Cell viability and nitric oxide production were evaluated by MTT assay and the Griess method, respectively. The neurotoxicities produced by all three hypoxia durations tested were significantly inhibited by 0.5 μM Noscapine. Increasing Noscapine concentration up to 2.5 μM produced a concentration-dependent inhibition of neurotoxicity. Pretreatment of cells with MK-801 (10 μM), a non-competitive NMDA antagonist, and nimodipine (10nM), an L-type Ca(2+) channel blockers, increased cell viability after 30 min OGD, while the application of NBQX (30 μM), a selective AMPA-kainate receptor antagonist partially attenuated cell injury. Subsequently, cells treated with Noscapine in the presence of thapsigargin (1 μM), an inhibitor of endoplasmic retireticulum Ca(2+) ATPases. After 60 min OGD, Noscapine could inhibit the cell damage induced by thapsigargin. However, Noscapine could not reduce cell damage induced by 240 min OGD in the presence of thapsigargin. Noscapine attenuated nitric oxide (NO) production in cortical neurons after 30 min OGD. We concluded that Noscapine had a neuroprotective effect, which could be due to its interference with multiple targets in the excitotoxicity process. These effects could be mediated partially by a decrease in NO production and the modulation of intracellular calcium levels. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  • Neuroprotective effect of Noscapine on cerebral oxygen–glucose deprivation injury
    Pharmacological reports : PR, 2014
    Co-Authors: Gelareh Vahabzadeh, Nahid Rahbar-roshandel, Soltan-ahmad Ebrahimi, Massoud Mahmoudian
    Abstract:

    Abstract Background The present study aims to investigate the effect of Noscapine (0.5–2.5 μM), an alkaloid from the opium poppy, on primary murine fetal cortical neurons exposed to oxygen–glucose deprivation (OGD), an in vitro model of ischemia. Methods Cells were transferred to glucose-free DMEM and were exposed to hypoxia in a small anaerobic chamber. Cell viability and nitric oxide production were evaluated by MTT assay and the Griess method, respectively. Results The neurotoxicities produced by all three hypoxia durations tested were significantly inhibited by 0.5 μM Noscapine. Increasing Noscapine concentration up to 2.5 μM produced a concentration-dependent inhibition of neurotoxicity. Pretreatment of cells with MK-801 (10 μM), a non-competitive NMDA antagonist, and nimodipine (10 nM), an L-type Ca 2+ channel blockers, increased cell viability after 30 min OGD, while the application of NBQX (30 μM), a selective AMPA-kainate receptor antagonist partially attenuated cell injury. Subsequently, cells treated with Noscapine in the presence of thapsigargin (1 μM), an inhibitor of endoplasmic retireticulum Ca 2+ ATPases. After 60 min OGD, Noscapine could inhibit the cell damage induced by thapsigargin. However, Noscapine could not reduce cell damage induced by 240 min OGD in the presence of thapsigargin. Noscapine attenuated nitric oxide (NO) production in cortical neurons after 30 min OGD. Conclusions We concluded that Noscapine had a neuroprotective effect, which could be due to its interference with multiple targets in the excitotoxicity process. These effects could be mediated partially by a decrease in NO production and the modulation of intracellular calcium levels.

Zhong-ze Fang – One of the best experts on this subject based on the ideXlab platform.

  • metabolic map and bioactivation of the anti tumour drug Noscapine
    British Journal of Pharmacology, 2012
    Co-Authors: Zhong-ze Fang, Kristopher W. Krausz, Jie Cheng, Naoki Tanaka, Frank J. Gonzalez
    Abstract:

    BACKGROUND AND PURPOSE Noscapine is a promising anti-tumour agent. The purpose of the present study was to describe the metabolic map and investigate the bioactivation of Noscapine. EXPERIMENTAL APPROACH Ultra-performance liquid chrochromatography coupled with electrospray ioniionization quadrupole time-of-flight mass spectrometry-based metabolomics was used to analyse the in vitro incubation mixtures, urine and faeces samples from mice treated with Noscapine. Recombinant drug-metabolizing enzymes were employed to identify those involved in Noscapine metabolism. Hepatic GSH levels and serum biochemistry were also carried out to determine reactive metabolites of Noscapine. KEY RESULTS Several novel phase I metabolites of Noscapine were detected after oral gavage of mice, including an N-demethylated metabolite, two hydroxylated metabolites, one metabolite undergoing both demethylation and cleavage of the methylenedioxy group and a bis-demethylated metabolite. Additionally, several novel glucuronides were detected, and their structures were elucidated through MS/MS fragmentology. Recombinant enzymes screening showed the involvement of several cytochromes P450, flavin-containing mono-oxygenase 1 and the UDP-glucuronosyltransferases UGT1A1, UGT1A3, UGT1A9 and UGT2B7, in Noscapine metabolism. In vitro glutathione trapping revealed the existence of an ortho-quinone reactive intermediate formed through further oxidation of a catechol metabolite. However, this bioactivation process of Noscapine does not occur in vivo. Similar to this result, altered glutathione levels in liver and serum biochemistry revealed no evidence of hepatic damage, thus indicating that, at least in mice, Noscapine does not induce hepatotoxicity through bioactivation. CONCLUSIONS AND IMPLICATIONS A comprehensive metabolic map and bioactivation evaluation provides important information for the development of Noscapine as an anti-tumour drug.

  • Metabolic map and bioactivation of the anti‐tumour drug Noscapine
    British journal of pharmacology, 2012
    Co-Authors: Zhong-ze Fang, Kristopher W. Krausz, Jie Cheng, Naoki Tanaka, Frank J. Gonzalez
    Abstract:

    BACKGROUND AND PURPOSE Noscapine is a promising anti-tumour agent. The purpose of the present study was to describe the metabolic map and investigate the bioactivation of Noscapine. EXPERIMENTAL APPROACH Ultra-performance liquid chrochromatography coupled with electrospray ioniionization quadrupole time-of-flight mass spectrometry-based metabolomics was used to analyse the in vitro incubation mixtures, urine and faeces samples from mice treated with Noscapine. Recombinant drug-metabolizing enzymes were employed to identify those involved in Noscapine metabolism. Hepatic GSH levels and serum biochemistry were also carried out to determine reactive metabolites of Noscapine. KEY RESULTS Several novel phase I metabolites of Noscapine were detected after oral gavage of mice, including an N-demethylated metabolite, two hydroxylated metabolites, one metabolite undergoing both demethylation and cleavage of the methylenedioxy group and a bis-demethylated metabolite. Additionally, several novel glucuronides were detected, and their structures were elucidated through MS/MS fragmentology. Recombinant enzymes screening showed the involvement of several cytochromes P450, flavin-containing mono-oxygenase 1 and the UDP-glucuronosyltransferases UGT1A1, UGT1A3, UGT1A9 and UGT2B7, in Noscapine metabolism. In vitro glutathione trapping revealed the existence of an ortho-quinone reactive intermediate formed through further oxidation of a catechol metabolite. However, this bioactivation process of Noscapine does not occur in vivo. Similar to this result, altered glutathione levels in liver and serum biochemistry revealed no evidence of hepatic damage, thus indicating that, at least in mice, Noscapine does not induce hepatotoxicity through bioactivation. CONCLUSIONS AND IMPLICATIONS A comprehensive metabolic map and bioactivation evaluation provides important information for the development of Noscapine as an anti-tumour drug.

  • Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Zhong-ze Fang, Yanyan Zhang, Guang-bo Ge, Si-cheng Liang, Ling Yang
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Clinical cases reported to the Swedish adverse drug interactions register (SWEDIS) indicated that drug–drug interaction (DDI) existed when warfarin was co-administered with Noscapine. • In vitro testing with recombinant human enzyme showed that Noscapine inhibited CYP3A4 and CYP2C9 with an IC50 of around 1 µm. • However, the clinical relevance of these in vitro data remains to be explored. WHAT THIS STUDY ADDS • Noscapine was demonstrated to be both a reversible inhibitor and a time-dependent inhibitor to CYP3A4 and CYP2C9. • DDI magnitude predicted from reversible inhibition and time-dependent inhibition (TDI) kinetic parameters showed that the TDI might be a noteworthy factor resulting in clinical Noscapinewarfarin interaction. AIMS To investigate the inhibition potential and kinetic information of Noscapine to seven CYP isoforms and extrapolate in vivo Noscapinewarfarin interaction magnitude from in vitro data. METHODS The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with Noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of Noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo Noscapinewarfarin interaction magnitude from in vitro data. RESULTS Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC50 of 10.8 ± 2.5 µm and 13.3 ± 1.2 µm. Kinetic analysis showed that inhibition of CYP2C9 by Noscapine was best fit to a noncompetitive type with Ki value of 8.8 µm, while inhibition of CYP3A4 by Noscapine was best fit to a competitive manner with Ki value of 5.2 µm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (KI and kinact) were calculated to be 9.3 µm and 0.06 min−1 for CYP3A4 and 8.9 µm and 0.014 min−1 for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using Cmax or 0.5% and 0.4% using unbound Cmax with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using Cmax or 41.8% and 32.7% using unbound Cmax with TDI prediction equation. CONCLUSIONS TDI of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapinewarfarin interaction.

Ling Yang – One of the best experts on this subject based on the ideXlab platform.

  • Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Zhong-ze Fang, Yanyan Zhang, Guang-bo Ge, Si-cheng Liang, Ling Yang
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Clinical cases reported to the Swedish adverse drug interactions register (SWEDIS) indicated that drug–drug interaction (DDI) existed when warfarin was co-administered with Noscapine. • In vitro testing with recombinant human enzyme showed that Noscapine inhibited CYP3A4 and CYP2C9 with an IC50 of around 1 µm. • However, the clinical relevance of these in vitro data remains to be explored. WHAT THIS STUDY ADDS • Noscapine was demonstrated to be both a reversible inhibitor and a time-dependent inhibitor to CYP3A4 and CYP2C9. • DDI magnitude predicted from reversible inhibition and time-dependent inhibition (TDI) kinetic parameters showed that the TDI might be a noteworthy factor resulting in clinical Noscapine–warfarin interaction. AIMS To investigate the inhibition potential and kinetic information of Noscapine to seven CYP isoforms and extrapolate in vivo Noscapine-warfarin interaction magnitude from in vitro data. METHODS The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with Noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of Noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo Noscapine–warfarin interaction magnitude from in vitro data. RESULTS Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC50 of 10.8 ± 2.5 µm and 13.3 ± 1.2 µm. Kinetic analysis showed that inhibition of CYP2C9 by Noscapine was best fit to a noncompetitive type with Ki value of 8.8 µm, while inhibition of CYP3A4 by Noscapine was best fit to a competitive manner with Ki value of 5.2 µm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (KI and kinact) were calculated to be 9.3 µm and 0.06 min−1 for CYP3A4 and 8.9 µm and 0.014 min−1 for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using Cmax or 0.5% and 0.4% using unbound Cmax with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using Cmax or 41.8% and 32.7% using unbound Cmax with TDI prediction equation. CONCLUSIONS TDI of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction.

  • time dependent inhibition tdi of cyp3a4 and cyp2c9 by Noscapine potentially explains clinical Noscapine warfarin interaction
    British Journal of Clinical Pharmacology, 2010
    Co-Authors: Zhong-ze Fang, Yanyan Zhang, Si-cheng Liang, Hong Huo, Ling Yang
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Clinical cases reported to the Swedish adverse drug interactions register (SWEDIS) indicated that drug–drug interaction (DDI) existed when warfarin was co-administered with Noscapine. • In vitro testing with recombinant human enzyme showed that Noscapine inhibited CYP3A4 and CYP2C9 with an IC50 of around 1 µm. • However, the clinical relevance of these in vitro data remains to be explored. WHAT THIS STUDY ADDS • Noscapine was demonstrated to be both a reversible inhibitor and a time-dependent inhibitor to CYP3A4 and CYP2C9. • DDI magnitude predicted from reversible inhibition and time-dependent inhibition (TDI) kinetic parameters showed that the TDI might be a noteworthy factor resulting in clinical Noscapinewarfarin interaction. AIMS To investigate the inhibition potential and kinetic information of Noscapine to seven CYP isoforms and extrapolate in vivo Noscapinewarfarin interaction magnitude from in vitro data. METHODS The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with Noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of Noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo Noscapinewarfarin interaction magnitude from in vitro data. RESULTS Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC50 of 10.8 ± 2.5 µm and 13.3 ± 1.2 µm. Kinetic analysis showed that inhibition of CYP2C9 by Noscapine was best fit to a noncompetitive type with Ki value of 8.8 µm, while inhibition of CYP3A4 by Noscapine was best fit to a competitive manner with Ki value of 5.2 µm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (KI and kinact) were calculated to be 9.3 µm and 0.06 min−1 for CYP3A4 and 8.9 µm and 0.014 min−1 for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using Cmax or 0.5% and 0.4% using unbound Cmax with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using Cmax or 41.8% and 32.7% using unbound Cmax with TDI prediction equation. CONCLUSIONS TDI of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapinewarfarin interaction.

  • Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
    British journal of clinical pharmacology, 2010
    Co-Authors: Zhong-ze Fang, Yanyan Zhang, Si-cheng Liang, Hong Huo, Ling Yang
    Abstract:

    To investigate the inhibition potential and kinetic information of Noscapine to seven CYP isoforms and extrapolate in vivo Noscapinewarfarin interaction magnitude from in vitro data. The activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co- or preincubation with Noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of Noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo Noscapinewarfarin interaction magnitude from in vitro data. Among seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC(50) of 10.8 +/- 2.5 microm and 13.3 +/- 1.2 microm. Kinetic analysis showed that inhibition of CYP2C9 by Noscapine was best fit to a noncompetitive type with K(i) value of 8.8 microm, while inhibition of CYP3A4 by Noscapine was best fit to a competitive manner with K(i) value of 5.2 microm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (K(I) and k(inact)) were calculated to be 9.3 microm and 0.06 min(-1) for CYP3A4 and 8.9 microm and 0.014 min(-1) for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using C(max) or 0.5% and 0.4% using unbound C(max) with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using C(max) or 41.8% and 32.7% using unbound C(max) with TDI prediction equation. TDI of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapinewarfarin interaction.