This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry(LC–MS/MS)and its application to a pharmacokinetic study involving single and multi...This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry(LC–MS/MS)and its application to a pharmacokinetic study involving single and multiple intravenous infusions to healthy Chinese volunteers.After sample preparation of plasma by liquid–liquid extraction with ethyl acetate,the analyte and internal standard,urapidil,were separated by reversed phase chromatography in a run time of 4 min and detected by positive ion electrospray ionization followed by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 326.2-308.1 for ifenprodil and m/z 388.4-205.3 for IS.The assay was linear in the concentration range 0.2–50.0 ng/mL with recovery 476.4%.In the pharmacokinetic study of single intravenous infusions of 5,10 and 15 mg ifenprodil,peak plasma concentrations and areas under the plasma concentration–time curve were both linearly related to dose.In the pharmacokinetic study of multiple once daily intravenous infusions of 10 mg ifenprodil for 7 days,pharmacokinetic parameters were similar to those after the single dose showing that ifenprodil does not accumulate on repeated administration.展开更多
The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating rest...The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.展开更多
文摘This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry(LC–MS/MS)and its application to a pharmacokinetic study involving single and multiple intravenous infusions to healthy Chinese volunteers.After sample preparation of plasma by liquid–liquid extraction with ethyl acetate,the analyte and internal standard,urapidil,were separated by reversed phase chromatography in a run time of 4 min and detected by positive ion electrospray ionization followed by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 326.2-308.1 for ifenprodil and m/z 388.4-205.3 for IS.The assay was linear in the concentration range 0.2–50.0 ng/mL with recovery 476.4%.In the pharmacokinetic study of single intravenous infusions of 5,10 and 15 mg ifenprodil,peak plasma concentrations and areas under the plasma concentration–time curve were both linearly related to dose.In the pharmacokinetic study of multiple once daily intravenous infusions of 10 mg ifenprodil for 7 days,pharmacokinetic parameters were similar to those after the single dose showing that ifenprodil does not accumulate on repeated administration.
文摘The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.
