Flupirtine maleate, a pharmaceutical compound for treating psychotic disease in clinics, has seven polymorphs. Form A, with better crystal stability and bioavailability, has been widely used as the pharmaceutical crys...Flupirtine maleate, a pharmaceutical compound for treating psychotic disease in clinics, has seven polymorphs. Form A, with better crystal stability and bioavailability, has been widely used as the pharmaceutical crystal form. Unfortunately, it is usually found in a polymorphic mixture with form B. In this study, pure crystal forms of A and B were prepared and characterized by X-ray powder diffraction （XRPD）, Fourier transform infrared spectroscopy （FT-IR） and thermal analysis. An XRPD-based method for the quantitative determination of the amount of the flupirtine maleate polymorphs form A and form B was also established through a systematic optimization of instrumental parameters. The results of the analytical methodology validation showed that the XPRD method had a broad quantitative range of 0- 100% （w/w）, good linear relationship, with R2= 0.999, excellent repeatability and precision and low limits of detection （LoD） of 0.15% （w/w） and quantification （LoQ） of 0.5% （w/w）. The results also showed that the single-peak method was not as good as the whole pattern in reducing the influence of the preferred orientation, but this can be compensated for by a systematic optimization of instrumental parameters and validating the analytical methodology to reduce errors and obtain a good, repeatable, sensitive, and accurate method. This XRPD method can be used to analyze mixtures of flupirtine maleate polymorphs （forms A and B） quantitatively and control the quality of the bulk drug.展开更多
Objective： Flupirtine is a non-opioid analgesic without antipyretic or antiphlogistic properties but with favorable tolerability in humans. ＂Ibis analgesic also exhibits neuroprotective activities. Furthermore, flup...Objective： Flupirtine is a non-opioid analgesic without antipyretic or antiphlogistic properties but with favorable tolerability in humans. ＂Ibis analgesic also exhibits neuroprotective activities. Furthermore, flupirtine antagonizes glutamate- and . , 2＋ NMDA-mduced mtracellular levels of Ca and counteracts the effects of focal cerebral Lscherma. Although fluplrtme has been used to relieve pain caused by different diseases and clinical procedures, information on the safety and efficacy of flupirtine is limited. ＂fhe present study was conducted to investigate the neuroprotective effects of flupirtine on U373 malignant glioma （MG） cell lines. Methods： Cellviability and cell cycle analysis was performed by MTF assay and flow cytomet-,＇y, respectively. Results： Variations in the growth of U373 MG cells in $ mM N-methyl-D-aspartate （NMDA）, 1 mM flupirtine, and combined treatment indicated the antagonistic effects of NMDA and flupirtine on MG cell lines. The variation in the percentage of gated cellpopulation in different cell cycle phases showed significant variations after 48 h of treatment. Conclusion： Flupirtine has neuroprotective effect of on U373 MG cells, which limits its use in the pain management of brain tumors. This property warrants further studies using animal models and large-scale clinical trials.展开更多
OBJECTIVE To assess whether N-acetylcysteine(NAC)and reduced glutathione(GSH)are effective in reversing flupirtine-induced hepatotoxicity and whether they have other beneficial effects when combined with flupirtine.ME...OBJECTIVE To assess whether N-acetylcysteine(NAC)and reduced glutathione(GSH)are effective in reversing flupirtine-induced hepatotoxicity and whether they have other beneficial effects when combined with flupirtine.METHODS The analgesic effects of NAC and flupirtine were first evaluated in carrageenaninduced inflammatory pain and paclitaxel-induced neuropathic pain.The combination subthreshold⁃ing approach was then used to determine whether the combination of NAC and flupirtine produced synergistic analgesic effects.Hepatotoxicity markers and histopathological examination of the liver were used to assess the efficacy of NAC and GSH in reversing flupirtine-induced hepato⁃toxicity.Finally,the effect of GSH on the safe range of flupirtine was assessed in an acute tox⁃icity assay.RESULTS Flupirtine and NAC pro⁃duced dose-dependent antiallodynic effects evoked by carrageenan and paclitaxel in mice.In the above model,the combination of NAC and flupirtine produced an unexpected synergistic analgesic effect.There were no significant differ⁃ences observed in the hepatotoxicity markers and liver histopathology between the experimen⁃tal group and the control group under NAC and GSH treatment.Finally,GSH(200 mg·kg^(-1))expanded the therapeutic index of flupirtine by 1.77 times.CONCLUSION NAC and GSH are effective in preventing liver damage caused by long-term flupirtine use,which provides a solu⁃tion for the safe and effective treatment of chronic pain with flupirtine.In addition,the other benefi⁃cial effects of NAC and GSH when combined with flupirtine may provide the basis for the devel⁃opment of a new therapy with minimal sideeffects and good efficacy.展开更多
In the present study, we developed a simple, sensitive, precise, and accurate liquid chromatography-tandem mass spectrometric(LC-MS/MS) method and validated such approach for simultaneous determination of flupirtine a...In the present study, we developed a simple, sensitive, precise, and accurate liquid chromatography-tandem mass spectrometric(LC-MS/MS) method and validated such approach for simultaneous determination of flupirtine and its active metabolite D-13223 in human plasma. The flupirtine, D-13223, and stable isotope internal standard(IS) were extracted from plasma samples by liquid-liquid extraction and chromatographed on a C18 column with a mobile phase consisting of acetonitrile–water–ammonia(55:45:0.1, v/v/v) at a flow rate of 0.25 m L/min. Detection was performed on a triple quadrupole tandem mass spectrometer with an electrospray ionization source(ESI) by multiple reaction monitoring(MRM) in positive ion mode. The linear calibration curves were obtained within the concentration range of 10.00–2000.00 ng/m L for flupirtine and 2.00–400.00 ng/m L for D-13223. The intra-and inter-run RSD, calculated from quality control(QC) samples, was less than 9.26% for flupirtine and D-13223. The accuracy was –5.80%–3.31% for flupirtine and D-13223. The extraction recoveries of flupirtine, D-13223, and their IS were all between 88.3%–97.2%. The method was successfully applied to investigate the pharmacokinetic profiles of flupirtine and its active metabolite D-13223 in human plasma following peroral administration of 100 mg flupirtine maleate capsules in healthy male Chinese volunteers.展开更多
Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently,this dru...Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently,this drug has been used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and non-steroidal anti-inflammatory drug and is well tolerated. The pharmacological profile exhibited involves actions on several cellular targets,including Kv7 channels,Gprotein-regulated inwardly rectifying K channels and γ-aminobutyric acid type A receptors,but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine. Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia,flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant,a neuroprotectant,skeletal and smooth muscle relaxant,in treatment of auditory and visual disorders,and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. Identification of molecules exhibiting specificity for the pharmacological targets(e.g.,Kv7 isoforms) involved in the actions of flupirtine will provide further insight into clinical applications.Whether the broad-spectrum pharmacology of flupirtine or target-specific actions is preferential to gain benefit,especially in complex clinical conditions,requires further investigation. This review will consider recent advancement in understanding of the pharmacological profile and related clinical applications of flupirtine.展开更多
Fibromyalgia is characterized by the primary symptomsof persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current ...Fibromyalgia is characterized by the primary symptomsof persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current available therapies. An involvement of K^+ channels in the pathophysiology of fibromyalgia is emerging and supported by drug treatments for this condition exhibiting action at these molecular processes. K^+ channels constitute potential novel target candidates for pain therapy offering peripheral and/or central actions. The Kv7 channel activators, flupirtine and retigabine, have exhibited pharmacological profiles compatible to the requirements needed for use as a therapeutic approach to fibromyalgia. Clinical trials to address the multidimensional challenges of fibromyalgia with flupirtine and retigabine will provide important insight to the role of K^+ channels in this condition.展开更多
基金supported by the Major Program of Ministry of Science and Technology of China(No:2015ZX09J15104-003002)
文摘Flupirtine maleate, a pharmaceutical compound for treating psychotic disease in clinics, has seven polymorphs. Form A, with better crystal stability and bioavailability, has been widely used as the pharmaceutical crystal form. Unfortunately, it is usually found in a polymorphic mixture with form B. In this study, pure crystal forms of A and B were prepared and characterized by X-ray powder diffraction （XRPD）, Fourier transform infrared spectroscopy （FT-IR） and thermal analysis. An XRPD-based method for the quantitative determination of the amount of the flupirtine maleate polymorphs form A and form B was also established through a systematic optimization of instrumental parameters. The results of the analytical methodology validation showed that the XPRD method had a broad quantitative range of 0- 100% （w/w）, good linear relationship, with R2= 0.999, excellent repeatability and precision and low limits of detection （LoD） of 0.15% （w/w） and quantification （LoQ） of 0.5% （w/w）. The results also showed that the single-peak method was not as good as the whole pattern in reducing the influence of the preferred orientation, but this can be compensated for by a systematic optimization of instrumental parameters and validating the analytical methodology to reduce errors and obtain a good, repeatable, sensitive, and accurate method. This XRPD method can be used to analyze mixtures of flupirtine maleate polymorphs （forms A and B） quantitatively and control the quality of the bulk drug.
基金supported by an intramural grant from Sri Ramachandra University,Chennai
文摘Objective： Flupirtine is a non-opioid analgesic without antipyretic or antiphlogistic properties but with favorable tolerability in humans. ＂Ibis analgesic also exhibits neuroprotective activities. Furthermore, flupirtine antagonizes glutamate- and . , 2＋ NMDA-mduced mtracellular levels of Ca and counteracts the effects of focal cerebral Lscherma. Although fluplrtme has been used to relieve pain caused by different diseases and clinical procedures, information on the safety and efficacy of flupirtine is limited. ＂fhe present study was conducted to investigate the neuroprotective effects of flupirtine on U373 malignant glioma （MG） cell lines. Methods： Cellviability and cell cycle analysis was performed by MTF assay and flow cytomet-,＇y, respectively. Results： Variations in the growth of U373 MG cells in $ mM N-methyl-D-aspartate （NMDA）, 1 mM flupirtine, and combined treatment indicated the antagonistic effects of NMDA and flupirtine on MG cell lines. The variation in the percentage of gated cellpopulation in different cell cycle phases showed significant variations after 48 h of treatment. Conclusion： Flupirtine has neuroprotective effect of on U373 MG cells, which limits its use in the pain management of brain tumors. This property warrants further studies using animal models and large-scale clinical trials.
基金Priority Academic Program Development of Jiangsu Higher Education Institutions(2022JSPAPD006)。
文摘OBJECTIVE To assess whether N-acetylcysteine(NAC)and reduced glutathione(GSH)are effective in reversing flupirtine-induced hepatotoxicity and whether they have other beneficial effects when combined with flupirtine.METHODS The analgesic effects of NAC and flupirtine were first evaluated in carrageenaninduced inflammatory pain and paclitaxel-induced neuropathic pain.The combination subthreshold⁃ing approach was then used to determine whether the combination of NAC and flupirtine produced synergistic analgesic effects.Hepatotoxicity markers and histopathological examination of the liver were used to assess the efficacy of NAC and GSH in reversing flupirtine-induced hepato⁃toxicity.Finally,the effect of GSH on the safe range of flupirtine was assessed in an acute tox⁃icity assay.RESULTS Flupirtine and NAC pro⁃duced dose-dependent antiallodynic effects evoked by carrageenan and paclitaxel in mice.In the above model,the combination of NAC and flupirtine produced an unexpected synergistic analgesic effect.There were no significant differ⁃ences observed in the hepatotoxicity markers and liver histopathology between the experimen⁃tal group and the control group under NAC and GSH treatment.Finally,GSH(200 mg·kg^(-1))expanded the therapeutic index of flupirtine by 1.77 times.CONCLUSION NAC and GSH are effective in preventing liver damage caused by long-term flupirtine use,which provides a solu⁃tion for the safe and effective treatment of chronic pain with flupirtine.In addition,the other benefi⁃cial effects of NAC and GSH when combined with flupirtine may provide the basis for the devel⁃opment of a new therapy with minimal sideeffects and good efficacy.
文摘In the present study, we developed a simple, sensitive, precise, and accurate liquid chromatography-tandem mass spectrometric(LC-MS/MS) method and validated such approach for simultaneous determination of flupirtine and its active metabolite D-13223 in human plasma. The flupirtine, D-13223, and stable isotope internal standard(IS) were extracted from plasma samples by liquid-liquid extraction and chromatographed on a C18 column with a mobile phase consisting of acetonitrile–water–ammonia(55:45:0.1, v/v/v) at a flow rate of 0.25 m L/min. Detection was performed on a triple quadrupole tandem mass spectrometer with an electrospray ionization source(ESI) by multiple reaction monitoring(MRM) in positive ion mode. The linear calibration curves were obtained within the concentration range of 10.00–2000.00 ng/m L for flupirtine and 2.00–400.00 ng/m L for D-13223. The intra-and inter-run RSD, calculated from quality control(QC) samples, was less than 9.26% for flupirtine and D-13223. The accuracy was –5.80%–3.31% for flupirtine and D-13223. The extraction recoveries of flupirtine, D-13223, and their IS were all between 88.3%–97.2%. The method was successfully applied to investigate the pharmacokinetic profiles of flupirtine and its active metabolite D-13223 in human plasma following peroral administration of 100 mg flupirtine maleate capsules in healthy male Chinese volunteers.
文摘Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently,this drug has been used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and non-steroidal anti-inflammatory drug and is well tolerated. The pharmacological profile exhibited involves actions on several cellular targets,including Kv7 channels,Gprotein-regulated inwardly rectifying K channels and γ-aminobutyric acid type A receptors,but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine. Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia,flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant,a neuroprotectant,skeletal and smooth muscle relaxant,in treatment of auditory and visual disorders,and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. Identification of molecules exhibiting specificity for the pharmacological targets(e.g.,Kv7 isoforms) involved in the actions of flupirtine will provide further insight into clinical applications.Whether the broad-spectrum pharmacology of flupirtine or target-specific actions is preferential to gain benefit,especially in complex clinical conditions,requires further investigation. This review will consider recent advancement in understanding of the pharmacological profile and related clinical applications of flupirtine.
文摘Fibromyalgia is characterized by the primary symptomsof persistent diffuse pain, fatigue, sleep disturbance and cognitive dysfunction. Persistent pain conditions, such as fibromyalgia, are often refractory to current available therapies. An involvement of K^+ channels in the pathophysiology of fibromyalgia is emerging and supported by drug treatments for this condition exhibiting action at these molecular processes. K^+ channels constitute potential novel target candidates for pain therapy offering peripheral and/or central actions. The Kv7 channel activators, flupirtine and retigabine, have exhibited pharmacological profiles compatible to the requirements needed for use as a therapeutic approach to fibromyalgia. Clinical trials to address the multidimensional challenges of fibromyalgia with flupirtine and retigabine will provide important insight to the role of K^+ channels in this condition.
