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Massoud Mahmoudian - One of the best experts on this subject based on the ideXlab platform.
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The Effect of Noscapine on Oxygen-Glucose Deprivation on Primary Murine Cortical Neurons in High Glucose Condition.
Iranian journal of pharmaceutical research : IJPR, 2016Co-Authors: Gelareh Vahabzadeh, Soltan Ahmed Ebrahimi, Nahid Rahbar-roshandel, Massoud MahmoudianAbstract: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 ischemia in cortical neurons.
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Neuroprotective effect of Noscapine on cerebral oxygen–glucose deprivation injury
Pharmacological reports : PR, 2014Co-Authors: Gelareh Vahabzadeh, Nahid Rahbar-roshandel, Soltan-ahmad Ebrahimi, Massoud MahmoudianAbstract: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 reticulum 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.
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Neuroprotective effect of Noscapine on cerebral oxygen–glucose deprivation injury
Pharmacological reports : PR, 2014Co-Authors: Gelareh Vahabzadeh, Nahid Rahbar-roshandel, Soltan-ahmad Ebrahimi, Massoud MahmoudianAbstract: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 reticulum 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.
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THE PROTECTIVE ACTIVITY OF Noscapine ON RENAL ISCHEMIA-REPERFUSION INJURY IN MALE WISTAR RAT
Iranian journal of basic medical sciences, 2014Co-Authors: Mehrangiz Khanmoradi, Nahid Aboutaleb, Seyyed Ali Mard, M. Nobakht, Massoud MahmoudianAbstract:Bradykinin is a part of the kinin-kallikrein system which is involved in ischemia-reperfusion injury via B1 and B2 receptors. Noscapine is a non-competitive antagonist of bradykinin receptors. Noscapine has been reported to to be able to protect some organs against ischemia-reperfusion injury but its effect on renal ischemia-reperfusion injury (RIR) in rats is unknown. Therefore, the present study was designed to evaluate the effect of Noscapine on renal ischemia-reperfusion injury in rats. Twenty four rats were randomly assigned to four groups; sham, RIR control, pre-and post-treatment with Noscapine. To induce RIR injury, 20 days after right nephrectomy, animals underwent a midline laparotomy and the renal artery was clamped for 40 min to induce ischemia, and the clamp was then removed to allow reperfusion for 48 hr. Animals received Noscapine or vehicle 1 hr before RIR or just prior to reperfusion. At the end of the experiment, animals were killed by cardiac exsanguination. Blood samples were collected to assess blood urea nitrogen (BUN) and creatinine. The kidneys were also removed for histopathlogical and western-blot analysis. Noscapine treatment 1 hr before RIR or just prior to reperfusion protects the renal tissue structure as compared with the control. The expression levels of the studied inflammatory mediators, TNF-α and MCP-1in pretreated-, and treated-Noscapine groups decreased as compared with the control group. The levels of BUN and creatinine in pre-, and post-treated Noscapine groups were significantly lower than in control animals. Noscapine protects renal tissue structure and function against RIR through down-regulation of the inflammatory mediators.
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THE PROTECTIVE ACTIVITY OF Noscapine ON RENAL ISCHEMIA-REPERFUSION INJURY IN MALE WISTAR RAT
Iranian journal of basic medical sciences, 2014Co-Authors: Mehrangiz Khanmoradi, Nahid Aboutaleb, Seyyed Ali Mard, M. Nobakht, Massoud MahmoudianAbstract:Objective(s):Bradykinin is a part of the kinin-kallikreinsystem which is involved in ischemia-reperfusion injury via B1 and B2 receptors.Noscapine is a non-competitive antagonist of bradykinin receptors. Noscapine has been reported to to be able to protect some organs against ischemia-reperfusion injury but its effect on renal ischemia-reperfusion injury (RIR) in rats is unknown. Therefore, the present study was designed to evaluate the effect of Noscapine on renal ischemia-reperfusion injury in rats. Materials and Methods: Twenty four rats were randomly assigned to four groups; sham, RIR control, pre-and post-treatment with Noscapine. To induce RIR injury, 20 days after right nephrectomy, animals underwent a midline laparotomy and the renal artery was clamped for 40 min to induce ischemia, and the clamp was then removed to allow reperfusion for 48 hr. Animals received Noscapine or vehicle 1 hr before RIR or just prior to reperfusion. At the end of the experiment, animals were killed by cardiac exsanguination. Blood samples were collected to assess blood urea nitrogen (BUN) and creatinine. The kidneys were also removed for histopathlogical and western-blot analysis. Results: Noscapine treatment 1 hr before RIR or just prior to reperfusion protects the renal tissue structure as compared with the control. The expression levels of the studied inflammatory mediators, TNF-α and MCP-1in pretreated-, and treated-Noscapine groups decreased as compared with the control group. The levels of BUN and creatinine in pre-, and post-treated Noscapine groups were significantly lower than in control animals. Conclusion: Noscapine protects renal tissue structure and function against RIR through down-regulation of the inflammatory mediators.
Zhong-ze Fang - One of the best experts on this subject based on the ideXlab platform.
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metabolic map and bioactivation of the anti tumour drug Noscapine
British Journal of Pharmacology, 2012Co-Authors: Zhong-ze Fang, Kristopher W. Krausz, Jie Cheng, Naoki Tanaka, Frank J. GonzalezAbstract: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 chromatography coupled with electrospray ionization 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.
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Metabolic map and bioactivation of the anti‐tumour drug Noscapine
British journal of pharmacology, 2012Co-Authors: Zhong-ze Fang, Kristopher W. Krausz, Jie Cheng, Naoki Tanaka, Frank J. GonzalezAbstract: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 chromatography coupled with electrospray ionization 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.
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Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
British Journal of Clinical Pharmacology, 2010Co-Authors: Zhong-ze Fang, Guang-bo Ge, Si-cheng Liang, Yanyan Zhang, Ling YangAbstract: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.
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time dependent inhibition tdi of cyp3a4 and cyp2c9 by Noscapine potentially explains clinical Noscapine warfarin interaction
British Journal of Clinical Pharmacology, 2010Co-Authors: Si-cheng Liang, Zhong-ze Fang, Yanyan Zhang, Hong Huo, Ling YangAbstract: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.
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Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
British journal of clinical pharmacology, 2010Co-Authors: Zhong-ze Fang, Si-cheng Liang, Yanyan Zhang, Hong Huo, Ling YangAbstract: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. 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. 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 Noscapine-warfarin interaction.
Ling Yang - One of the best experts on this subject based on the ideXlab platform.
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Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
British Journal of Clinical Pharmacology, 2010Co-Authors: Zhong-ze Fang, Guang-bo Ge, Si-cheng Liang, Yanyan Zhang, Ling YangAbstract: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.
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time dependent inhibition tdi of cyp3a4 and cyp2c9 by Noscapine potentially explains clinical Noscapine warfarin interaction
British Journal of Clinical Pharmacology, 2010Co-Authors: Si-cheng Liang, Zhong-ze Fang, Yanyan Zhang, Hong Huo, Ling YangAbstract: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.
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Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
British journal of clinical pharmacology, 2010Co-Authors: Zhong-ze Fang, Si-cheng Liang, Yanyan Zhang, Hong Huo, Ling YangAbstract: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. 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. 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 Noscapine-warfarin interaction.
Harish C. Joshi - One of the best experts on this subject based on the ideXlab platform.
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Copper(I) Mediated Facile Synthesis of Potent Tubulin Polymerization Inhibitor, 9-Amino-α-Noscapine from Natural α-Noscapine.
ChemInform, 2012Co-Authors: Naresh Kumar Manchukonda, Harish C. Joshi, Balasubramanian Sridhar, Pradeep K. Naik, Srinivas KantevariAbstract:Facile synthesis of 9-amino-α-Noscapine (II) is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-α-Noscapine (obtained by bromination of natural α-Noscapine) with sodium azide in DMSO in the presence of L-proline as an amino acid promoter.
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Noscapine induced apoptosis via downregulation of survivin in human neuroblastoma cells having wild type or null p53
PLOS ONE, 2012Co-Authors: Guoqing Cao, Shaotao Tang, Qiangsong Tong, Harish C. JoshiAbstract:Neuroblastoma is the most common extracranial solid tumor of childhood. It accounts for 15% of pediatric cancer deaths. Chemotherapy is the mainstay of treatment in children with advanced neuroblastoma. Noscapine, a nontoxic natural compound, can trigger apoptosis in many cancer types. We now show that p53 is dispensable for Noscapine-induced cell death in neuroblastoma cell lines, proapoptotic response to this promising chemopreventive agent is mediated by suppression of survivin protein expression. The Noscapine treatment increased levels of total and Ser15-phosphorylated p53 protein in SK-SY5Y cells, but the proapoptotic response to this agent was maintained even after knockdown of the p53 protein level. Exposure of SK-SY5Y and LA1-5S cells to Noscapine resulted in a marked decrease in protein and mRNA level of survivin as early as 12 hours after treatment. Ectopic expression of survivin conferred statistically significant protection against Noscapine-mediated cytoplasmic histone-associated apoptotic DNA fragmentation. Also, the Noscapine-induced apoptosis was modestly but statistically significantly augmented by RNA interference of survivin in both cell lines. Furthermore, Noscapine-induced apoptotic cell death was associated with activation of caspase-3 and cleavage of PARP. In conclusion, the present study provides novel insight into the molecular circuitry of Noscapine-induced apoptosis to indicate suppression of survivin expression as a critical mediator of this process.
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Copper(I) mediated facile synthesis of potent tubulin polymerization inhibitor, 9-amino-α-Noscapine from natural α-Noscapine.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Naresh Kumar Manchukonda, Harish C. Joshi, Balasubramanian Sridhar, Pradeep K. Naik, Srinivas KantevariAbstract:Abstract Facile synthesis of natural α-Noscapine analogue, 9-amino-α-Noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-α-Noscapine (obtained by bromination of natural α-Noscapine) with NaN3 in DMSO at 130 °C in the presence of l -proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-α-Noscapine and did not cleave the sensitive C–C bond between two heterocyclic phthalide and isoquinoline units.
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Rational design, synthesis and biological evaluations of amino-Noscapine: a high affinity tubulin-binding noscapinoid.
Journal of computer-aided molecular design, 2011Co-Authors: Pradeep Kumar Naik, Ritu Aneja, Ramesh Chandra, Biswa Prasun Chatterji, Surya N. Vangapandu, Srinivas Kanteveri, Harish C. JoshiAbstract:Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding free energies (ΔG (bind)) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model were in agreement with the experimental ΔG (bind) with average root mean square error of 0.082 kcal/mol. This LIE-SGB model guided us in designing a novel derivative of Noscapine, amino-Noscapine [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy isobenzo-furan-1(3H)-one] that has higher tubulin binding activity (predicted ΔG (bind) = -6.438 kcal/mol and experimental ΔG (bind) = -6.628 kcal/mol) than Noscapine, but does not significantly change the total extent of the tubulin subunit/polymer ratio. The modes of interaction of amino-Noscapine with the binding pocket of tubulin involved three hydrogen bonds and are distinct compared to Noscapine which involved only one hydrogen bond. Also the patterns of non-bonded interactions are albeit different between both the lignads. The 'blind docking' approach (docking of ligand with different binding sites of a protein and their evaluations) as well as the reasonable accuracy of calculating ΔG (bind) using LIE-SGB model constitutes the first evidence that this class of compounds binds to tubulin at a site overlapping with colchicine-binding site or close to it. Our results revealed that amino-Noscapine has better anti-tumor activity than Noscapine.
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Molecular modelling and competition binding study of Br-Noscapine and colchicine provide insight into noscapinoid-tubulin binding site
Journal of molecular graphics & modelling, 2011Co-Authors: Pradeep Kumar Naik, Seneha Santoshi, Ankit Rai, Harish C. JoshiAbstract:We have previously discovered the tubulin-binding anti-cancer properties of Noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: (1) in silico molecular docking studies of Br-Noscapine and Noscapine yield highest docking score with the well characterised colchicine-binding site from the co-crystal structure; (2) the molecular mechanics-generalized Born/surface area (MM-GB/SA) scoring results ΔΔG(bind-cald) for both Noscapine and Br-Noscapine (3.915 and 3.025 kcal/mol) are in reasonably good agreement with our experimentally determined binding affinity (ΔΔG(bind-Expt) of 3.570 and 2.988 kcal/mol, derived from K(d) values); and (3) Br-Noscapine competes with colchicine binding to tubulin. The simplest interpretation of these collective data is that Br-Noscapine binds tubulin at a site overlapping with, or very close to colchicine-binding site of tubulin. Although we cannot rule out a formal possibility that Br-Noscapine might bind to a site distinct and distant from the colchicine-binding site that might negatively influence the colchicine binding to tubulin.
Yanyan Zhang - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Inhibition Kinetics of (S)-warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy
Drug Metabolism and Disposition, 2013Co-Authors: Nan Zhang, Yanyan Zhang, Ryan P. Seguin, Kent L. Kunze, Hyunyoung JeongAbstract:Noscapine is an antitussive and potential anticancer drug. Clinically significant interactions between warfarin and Noscapine have been previously reported. In this study, to provide a basis for warfarin dosage adjustment, the inhibition kinetics of Noscapine against warfarin metabolism was characterized. Our enzyme kinetics data obtained from human liver microsomes and recombinant CYP2C9 proteins indicate that Noscapine is a competitive inhibitor of the (S)-warfarin 7-hydroxylation reaction by CYP2C9. Interestingly, Noscapine also inhibited (S)-warfarin metabolism in a NADPH- and time-dependent manner, and removal of unbound Noscapine and its metabolites by ultrafiltration did not reverse inhibition of (S)-warfarin metabolism by Noscapine, suggesting mechanism-based inhibition of CYP2C9 by Noscapine. Spectral scanning of the reaction between CYP2C9 and Noscapine revealed the formation of an absorption spectrum at 458 nm, indicating the formation of a metabolite-intermediate complex. Surprisingly, Noscapine is a 2- to 3-fold more efficient inactivator of CYP2C9.2 and CYP2C9.3 variants than it is of the wild type, by unknown mechanisms. Based on the inhibitory kinetic data, (S)-warfarin exposure is predicted to increase up to 7-fold (depending on CYP2C9 genotypes) upon Noscapine coadministration, mainly due to mechanism-based inactivation of CYP2C9 by Noscapine. Together, these results indicate that mechanism-based inhibition of CYP2C9 by Noscapine may dramatically alter pharmacokinetics of warfarin and provide a basis for warfarin dosage adjustment when Noscapine is coadministered.
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Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
British Journal of Clinical Pharmacology, 2010Co-Authors: Zhong-ze Fang, Guang-bo Ge, Si-cheng Liang, Yanyan Zhang, Ling YangAbstract: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.
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time dependent inhibition tdi of cyp3a4 and cyp2c9 by Noscapine potentially explains clinical Noscapine warfarin interaction
British Journal of Clinical Pharmacology, 2010Co-Authors: Si-cheng Liang, Zhong-ze Fang, Yanyan Zhang, Hong Huo, Ling YangAbstract: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.
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Time-dependent inhibition (TDI) of CYP3A4 and CYP2C9 by Noscapine potentially explains clinical Noscapine–warfarin interaction
British journal of clinical pharmacology, 2010Co-Authors: Zhong-ze Fang, Si-cheng Liang, Yanyan Zhang, Hong Huo, Ling YangAbstract: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. 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. 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 Noscapine-warfarin interaction.
