Simple, sensitive and accurate stability indicating analytical method for dronedarone has been developed and validated using RP-HPLC technique. Developed method is used to evaluate the assay and related substances of ...Simple, sensitive and accurate stability indicating analytical method for dronedarone has been developed and validated using RP-HPLC technique. Developed method is used to evaluate the assay and related substances of dronedarone drug substance and tablets (Multaq?). The drug substance was subjected to the stress conditions such as hydrolysis (acid and base), oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH) pre- scribed stress conditions to show the stability-indicating the nature of the method. Significant degradation was observed during acid and base hydrolysis, and peroxide degradation. The major degredants were identified by LC-MS, FTIR and 1H NMR spectral analysis. The chromatographic conditions were optimized using an impurity-spiked solution and the samples generated from forced degradation studies. In the developed HPLC method, the resolution between dronedar- one, process-related impurities, (namely Imp-1, Imp-2, Imp-3, Imp-4, Imp-5, Imp-6, Imp-7, Imp-8, Imp-9, Imp-10 and Imp-11) and degradation products were found to be greater than 1.5. The eleven potential process related impurities were separated on an Ascentis? Express C18 column (4.6 × 10 cm i.d., particle size 2.7 μm) at a flow rate of 1.2 mL.min-1. The LC method employed a linear gradient elution and the detection wavelength at 220 nm. The chroma- tographic behavior of all the impurities was examined under variable compositions of different solvents, temperatures and pH values.展开更多
The objective of the current study was to develop a validated, specific and stability-indicating reverse phase HPLC method for the quantitative determination of Dronedarone and its related substances. The determinatio...The objective of the current study was to develop a validated, specific and stability-indicating reverse phase HPLC method for the quantitative determination of Dronedarone and its related substances. The determination was done for active pharmaceutical ingredient and its pharmaceutical dosage forms in the presence of degradation products, and its process-related impurities. The drug was subjected to stress conditions of hydrolysis (acid and base), oxidation, photolysis and thermal degradation per International Conference on Harmonization (ICH) prescribed stress conditions to show the stability-indicating power of the method. Significant degradation was observed during acid, oxidative and photo stress studies. In the developed HPLC method, the resolution between Dronedarone and its process-related impurities was found to be greater than 2.0. Regression analysis shows an r value (correlation coefficient) of greater than 0.999 for Dronedarone and it’s all the five impurities. The chromatographic separation was achieved on a C8 stationary phase. The method employed a linear gradient elution and the detection wavelength was set at 288 nm. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.6%. The developed HPLC method was validated with respect to linearity, accuracy, precision and robustness.展开更多
Treatment options for patients with esophageal squamous cell carcinoma(ESCC)often result in poor prognosis and declining health-related quality of life.Screening FDA-approved drugs for cancer chemoprevention is a prom...Treatment options for patients with esophageal squamous cell carcinoma(ESCC)often result in poor prognosis and declining health-related quality of life.Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy.Here,we found that dronedarone,an antiarrhythmic drug,could inhibit the proliferation of ESCC cells.Moreover,we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells.Through computational docking models and pull-down assays,we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases.We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays.Subsequently,we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone.Furthermore,dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo.Thus,our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention.展开更多
Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adver...Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adverse effects(AEs)with poorly understood mechanisms.We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly,disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment.In this study,we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs.We first synthesized a deuterated analogue of dronedarone(termed poyendarone)and demonstrated that it neither inactivates CYP2J2,disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro.Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration.Next,we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat(BTB)variability reflective of proarrhythmic phenotype.In contrast,poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity.Importantly,poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF,while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk.Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.展开更多
Structure Activity Relationship forms the basis of Rational Drug Design in the circles of pharmaceutical and medicinal chemistry. Appropriate knowledge of functional outcomes of structural modifications is crucial in ...Structure Activity Relationship forms the basis of Rational Drug Design in the circles of pharmaceutical and medicinal chemistry. Appropriate knowledge of functional outcomes of structural modifications is crucial in conferring desired pharmacological properties to a chemical compound. Amiodarone is a classical antiarrythmic agent with a long list of adverse effects. This article attempts to review the structure activity relationship of some of the homologues of amiodarone in order to determine the most clinically desirable molecule.展开更多
文摘Simple, sensitive and accurate stability indicating analytical method for dronedarone has been developed and validated using RP-HPLC technique. Developed method is used to evaluate the assay and related substances of dronedarone drug substance and tablets (Multaq?). The drug substance was subjected to the stress conditions such as hydrolysis (acid and base), oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH) pre- scribed stress conditions to show the stability-indicating the nature of the method. Significant degradation was observed during acid and base hydrolysis, and peroxide degradation. The major degredants were identified by LC-MS, FTIR and 1H NMR spectral analysis. The chromatographic conditions were optimized using an impurity-spiked solution and the samples generated from forced degradation studies. In the developed HPLC method, the resolution between dronedar- one, process-related impurities, (namely Imp-1, Imp-2, Imp-3, Imp-4, Imp-5, Imp-6, Imp-7, Imp-8, Imp-9, Imp-10 and Imp-11) and degradation products were found to be greater than 1.5. The eleven potential process related impurities were separated on an Ascentis? Express C18 column (4.6 × 10 cm i.d., particle size 2.7 μm) at a flow rate of 1.2 mL.min-1. The LC method employed a linear gradient elution and the detection wavelength at 220 nm. The chroma- tographic behavior of all the impurities was examined under variable compositions of different solvents, temperatures and pH values.
文摘The objective of the current study was to develop a validated, specific and stability-indicating reverse phase HPLC method for the quantitative determination of Dronedarone and its related substances. The determination was done for active pharmaceutical ingredient and its pharmaceutical dosage forms in the presence of degradation products, and its process-related impurities. The drug was subjected to stress conditions of hydrolysis (acid and base), oxidation, photolysis and thermal degradation per International Conference on Harmonization (ICH) prescribed stress conditions to show the stability-indicating power of the method. Significant degradation was observed during acid, oxidative and photo stress studies. In the developed HPLC method, the resolution between Dronedarone and its process-related impurities was found to be greater than 2.0. Regression analysis shows an r value (correlation coefficient) of greater than 0.999 for Dronedarone and it’s all the five impurities. The chromatographic separation was achieved on a C8 stationary phase. The method employed a linear gradient elution and the detection wavelength was set at 288 nm. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.6%. The developed HPLC method was validated with respect to linearity, accuracy, precision and robustness.
基金funded by the National Natural Science Foundation of China(No.81872335)Central Plains Science and Technology Innovation Leading Talents(No.224200510015)+2 种基金National Natural Science Youth Foundation(No.81902486)Fundamental Research Project of key scientific research in Henan Province(No.23ZX007)Science and Technology Project of Henan Province(No.212102310187)。
文摘Treatment options for patients with esophageal squamous cell carcinoma(ESCC)often result in poor prognosis and declining health-related quality of life.Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy.Here,we found that dronedarone,an antiarrhythmic drug,could inhibit the proliferation of ESCC cells.Moreover,we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells.Through computational docking models and pull-down assays,we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases.We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays.Subsequently,we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone.Furthermore,dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo.Thus,our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention.
基金supported by the National University Heart Centre Singapore (NUHCS) Cardiovascular Research Institute (CVRI)Core Fund [Grant NUHSRO/2019/082/Core]SCEPTRE CG Seed Grant [Grant NMRC/CG/M008/2017, Singapore]+2 种基金Singapore Ministry of Education Tier 1 Academic Research Funding [Grant R-148-000-193-112]the National University of Singapore, Department of Pharmacy, Final Year Project Funding [Grant C148-000-003-001] provided to Eric Chun Yong Chanfrom Japan Society for the Promotion of Science (JSPS) KAKENHI [grant number 20K16136] provided to Ryuichi Kambayashi
文摘Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adverse effects(AEs)with poorly understood mechanisms.We previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly,disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET enrichment.In this study,we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac AEs.We first synthesized a deuterated analogue of dronedarone(termed poyendarone)and demonstrated that it neither inactivates CYP2J2,disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in vitro.Our patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by deuteration.Next,we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat(BTB)variability reflective of proarrhythmic phenotype.In contrast,poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 activity.Importantly,poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF,while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic risk.Our findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.
文摘Structure Activity Relationship forms the basis of Rational Drug Design in the circles of pharmaceutical and medicinal chemistry. Appropriate knowledge of functional outcomes of structural modifications is crucial in conferring desired pharmacological properties to a chemical compound. Amiodarone is a classical antiarrythmic agent with a long list of adverse effects. This article attempts to review the structure activity relationship of some of the homologues of amiodarone in order to determine the most clinically desirable molecule.
