Background: The prevalence of both atrial fibrillation (FA) and diabetes mellitus (DM) is increasing and they often occur together and constitute a high risk of thrombosis. Rivaroxaban is a Factor Xa inhibitor with a ...Background: The prevalence of both atrial fibrillation (FA) and diabetes mellitus (DM) is increasing and they often occur together and constitute a high risk of thrombosis. Rivaroxaban is a Factor Xa inhibitor with a rapid onset and disappearance of action after oral administration;it acts by inhibiting the active form of the coagulation factor. In order to reflect the effect of the action of Rivaroxaban, we used the prothrombin time (PT);however, it′s not the most accurate, but it is the one available in our community. Methods: This was a prospective, randomized, analyst-blinded, parallel group clinical study to verify the efficacy of Rivaroxaban Leti 20 mg (RL) (12 volunteers vs Rivaroxaban Bayer 20 mg (RB) (13 volunteers). The variables were determination of PT and Partial Thromboplastin Time (aPTT) at baseline and at 24, 48 and 72 hours after administering a daily dose of 20 mg for three days. The determination was carried out with the IDG method (Integrated Diagnostics Group Sanzay Corporation) with an International Sensitivity Index (ISI) of 1.17 PT and aPTT were taken before the first dose, and then, every day during the next 3 days, three hours after the ingestion of their daily dose at 7 am. Results: The 25 healthy volunteers were similar in age, BMI, and SBP/DBP level with a greater number of men in the Bayer group. The efficacy of rivaroxaban was similar in both groups with prolongation of PTT to the 2nd day of treatment with PT, and percentage changes from baseline (14.46 ± 0.97 for RB vs 14.17 ± 0.94 RL p: 0.45), PTT results and percentage changes from the base (RB: 34 ± 4.53 RL: 33.46 ± 2.82). The safety of rivaroxaban was good in both groups with no serious adverse events. The equivalence in the logarithmically transformed PT result (ln) on day two, Mean and CI (90%) 99.2 (94.4-104) and 100 (99.5-100.8);neither the means nor the 90% confidence intervals of the PT variable transformed logarithmically to ensure its normality, were far from the 80%-125% allowed for declaration of similarity. Conclusion: The test formulation Rivaroxaban Asarap<sup>?</sup> 20 mg, manufactured by Leti Laboratories, is interchangeable or bioequivalent in clinical and laboratory response to the reference formulation Xarelto<sup>?</sup> manufactured by Bayer Laboratories.展开更多
The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradual...The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradually.This process has taken the FDA seven years.Starting from the reduction of funding for animal of data from organ-on-a-chip solely for pharmacodynamic studies[[1],[2],[3]],to the explicit proposal of the animal-free approach for pharmacodynamic studies in the FDA Modernization Act in Reference[4],and to the indication in 2025 that safety studies should also prioritize safety research data from in vitro microphysiological systems[5],this demonstrates the FDAs determination to gradually achieve the animal-free approach and also signals a profound paradigm shift in the field of drug research and development.This policy direction not only addresses the requirements of ethics and technological advancement but may also reshape the entire new drug development industrial chain.展开更多
The aim of present study was to formulate and evaluate a self-microemulsifying drug delivery systems(SMEDDS)containing lovastatin and to further explore the ability of porous Neusilin■ US2 tablet as a solid carrier f...The aim of present study was to formulate and evaluate a self-microemulsifying drug delivery systems(SMEDDS)containing lovastatin and to further explore the ability of porous Neusilin■ US2 tablet as a solid carrier for SMEDDS.SMEDDS formulations of varying proportions of peceol,cremophor RH 40 and transcutol-P were selected and subjected to invitro evaluation,including dispersibility studies,droplet size,zeta potential measurement and release studies.The results indicated that the drug release profile of lovastatin from SMEDDS formulations was statistically significantly higher(p-value<0.05)than the plain lovastatin powder.Thermodynamic stability studies also confirmed the stability of the prepared SMEDDS formulations.The optimized formulation,which consists of 12% of peceol,44% of cremophor RH 40,and 44% of transcutol-P was loaded into directly compressed liquid loadable tablet of Neusilin■ US2 by simple adsorption method.In order to determine the ability of Neusilin®US2 as a suitable carrier pharmacodynamics study were also carried out in healthy diet induced hyperlipidemic rabbits.Animals were administered with both liquid SMEDDS and solid SMEDDS as well.From the results obtained,Neusilin■ was found to be a suitable carrier for SMEDDS and was equally effective in reducing the elevated lipid profile.In conclusion,liquid loadable tablet(LLT)is predicted to be a promising technique to deliver a liquid formulation in solid state.展开更多
OBJECTIVE: To explore the pharmacodynamic effects and potential mechanisms of Shuangling extract against ulcerative colitis(UC). METHODS: The bioinformatics method was used to predict the active ingredients and action...OBJECTIVE: To explore the pharmacodynamic effects and potential mechanisms of Shuangling extract against ulcerative colitis(UC). METHODS: The bioinformatics method was used to predict the active ingredients and action targets of Shuangling extract against UC in mice. And the biological experiments such as serum biochemical indexes and histopathological staining were used to verify the pharmacological effect and mechanism of Shuangling extract against UC in mice. RESULTS: The Shuangling extract reduced the levels of seruminterleukin-1β(IL-1β), tumor necrosis factor-α(TNF-N), interleukin-6(IL-6) and other inflammatory factors in UC mice and inhibited the inflammatory response. AKT Serine/threonine Kinase 1 and IL-6 may be the main targets of the anti-UC action of Shuangling extract, and the TNF signaling pathway, Forkhead box O signaling pathway and T-cell receptor signaling pathway may be the main signaling pathways. CONCLUSION: The Shuangling extract could inhibit the inflammatory response induced by UC and regulate intestinal immune function through multiple targets and multiple channels, which provided a new option and theoretical basis for anti-UC.展开更多
In the present study,we prepared nattokinase-loaded self-double-emulsifying drug delivery system(SDEDDS)and investigated its preliminary pharmacodynamics.The type and concentration of oil phase,inner aqueous phase and...In the present study,we prepared nattokinase-loaded self-double-emulsifying drug delivery system(SDEDDS)and investigated its preliminary pharmacodynamics.The type and concentration of oil phase,inner aqueous phase and emulsifier were screened to prepare optimum nattokinase-loaded SDEDDS.Next,the optimum formulations were characterized based on microstructure,volume-weighted mean droplet size,self-emulsifying rate,yield,storage stability,in vitro release and in vivo pharmacodynamics studies.The water/oil/watermultiple emulsions exhibited typicalmultiple structure,with relatively small volumeweighted mean droplet size 6.0±0.7μm and high self-emulsifying ability(self-emulsifying time<2 min).Encapsulation of nattokinase was up to 86.8±8.2%.The cumulative release of nattokinase within 8 h was about 30%,exhibiting a sustained release effect.The pharmacodynamics study indicated that nattokinase-loaded SDEDDS could significantly prolong the whole blood clotting time in mouse and effectively improve the carrageenan-induced tail thrombosis compared with nattokinase solution.Moreover,we showed that SDEDDS could successfully self-emulsify into water/oil/water multiple emulsions upon dilution in dispersion medium with gentle stirring and effectively protect nattokinase activity in gastric environment.Our findings suggested that SDEDDS could be a promising strategy for peptide and protein drugs by oral administration.展开更多
The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design.In this study,we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-ba...The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design.In this study,we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-based design to target the PB1-binding interface on PA.Biological evaluation of these compounds through a viral yield reduction assay revealed that compounds 27 and 31 both had a low micromolar range of the half maximal effective concentration(EC_(50))values against A/WSN/33(H1N1)(8.03 mmol/L for 27;14.6 mmol/L for 31),while the most potent candidate 24 had an EC_(50) value of 690 nM.Compound 24 was effective against different influenza strains including a pandemic H1N1 strain and an influenza B strain.Mechanistic studies confirmed that compound 24 bound PA with a K_(d) which equals to 1.88 mmol/L and disrupted the binding of PB1 to PA.The compound also decreased the lung viral titre in mice.In summary,we have identified a potent anti-influenza candidate with potency comparable to existing drugs and is effective against different viral strains.The therapeutic options for influenza infection have been limited by the occurrence of antiviral resistance,owing to the high mutation rate of viral proteins targeted by available drugs.To alleviate the public health burden of this issue,novel anti-influenza drugs are desired.In this study,we present our discovery of a novel class of indazolecontaining compounds which exhibited favourable potency against both influenza A and B viruses.The EC_(50) of the most potent compounds were within low micromolar to nanomolar concentrations.Furthermore,we show that the mouse lung viral titre decreased due to treatment with compound 24.Thus our findings identify promising candidates for further development of anti-influenza drugs suitable for clinical use.展开更多
Alzheimer’s disease(AD)is a common neurodegenerative disorder among the elderly,and BuChE has emerged as a potential therapeutic target.In this study,we reported the development of compound 8e,a selective reversible ...Alzheimer’s disease(AD)is a common neurodegenerative disorder among the elderly,and BuChE has emerged as a potential therapeutic target.In this study,we reported the development of compound 8e,a selective reversible BuChE inhibitor(eqBuChE IC_(50)=0.049 mmol/L,huBuChE IC_(50)=0.066 mmol/L),identified through extensive virtual screening and lead optimization.Compound 8e demonstrated favorable bloodebrain barrier permeability,good drug-likeness property and pronounced neuroprotective efficacy.Additionally,8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice.Further,8e significantly improved cognitive function in APP/PS1 transgenic mice.Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor(VLDLR),offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway.Thus,compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD,with significant implications for further exploration into its mechanisms of action and therapeutic applications.展开更多
文摘Background: The prevalence of both atrial fibrillation (FA) and diabetes mellitus (DM) is increasing and they often occur together and constitute a high risk of thrombosis. Rivaroxaban is a Factor Xa inhibitor with a rapid onset and disappearance of action after oral administration;it acts by inhibiting the active form of the coagulation factor. In order to reflect the effect of the action of Rivaroxaban, we used the prothrombin time (PT);however, it′s not the most accurate, but it is the one available in our community. Methods: This was a prospective, randomized, analyst-blinded, parallel group clinical study to verify the efficacy of Rivaroxaban Leti 20 mg (RL) (12 volunteers vs Rivaroxaban Bayer 20 mg (RB) (13 volunteers). The variables were determination of PT and Partial Thromboplastin Time (aPTT) at baseline and at 24, 48 and 72 hours after administering a daily dose of 20 mg for three days. The determination was carried out with the IDG method (Integrated Diagnostics Group Sanzay Corporation) with an International Sensitivity Index (ISI) of 1.17 PT and aPTT were taken before the first dose, and then, every day during the next 3 days, three hours after the ingestion of their daily dose at 7 am. Results: The 25 healthy volunteers were similar in age, BMI, and SBP/DBP level with a greater number of men in the Bayer group. The efficacy of rivaroxaban was similar in both groups with prolongation of PTT to the 2nd day of treatment with PT, and percentage changes from baseline (14.46 ± 0.97 for RB vs 14.17 ± 0.94 RL p: 0.45), PTT results and percentage changes from the base (RB: 34 ± 4.53 RL: 33.46 ± 2.82). The safety of rivaroxaban was good in both groups with no serious adverse events. The equivalence in the logarithmically transformed PT result (ln) on day two, Mean and CI (90%) 99.2 (94.4-104) and 100 (99.5-100.8);neither the means nor the 90% confidence intervals of the PT variable transformed logarithmically to ensure its normality, were far from the 80%-125% allowed for declaration of similarity. Conclusion: The test formulation Rivaroxaban Asarap<sup>?</sup> 20 mg, manufactured by Leti Laboratories, is interchangeable or bioequivalent in clinical and laboratory response to the reference formulation Xarelto<sup>?</sup> manufactured by Bayer Laboratories.
文摘The U.S.Food and Drug Administration(FDA)'s program documents regarding the animal-free approach for the efficacy,pharmacokinetics,and safety evaluation of new drug preclinical studies have been rolled out gradually.This process has taken the FDA seven years.Starting from the reduction of funding for animal of data from organ-on-a-chip solely for pharmacodynamic studies[[1],[2],[3]],to the explicit proposal of the animal-free approach for pharmacodynamic studies in the FDA Modernization Act in Reference[4],and to the indication in 2025 that safety studies should also prioritize safety research data from in vitro microphysiological systems[5],this demonstrates the FDAs determination to gradually achieve the animal-free approach and also signals a profound paradigm shift in the field of drug research and development.This policy direction not only addresses the requirements of ethics and technological advancement but may also reshape the entire new drug development industrial chain.
基金International Medical University(IMU),Malaysia for financially supporting the present work under the research grant number BPharm B0108_Res322011.
文摘The aim of present study was to formulate and evaluate a self-microemulsifying drug delivery systems(SMEDDS)containing lovastatin and to further explore the ability of porous Neusilin■ US2 tablet as a solid carrier for SMEDDS.SMEDDS formulations of varying proportions of peceol,cremophor RH 40 and transcutol-P were selected and subjected to invitro evaluation,including dispersibility studies,droplet size,zeta potential measurement and release studies.The results indicated that the drug release profile of lovastatin from SMEDDS formulations was statistically significantly higher(p-value<0.05)than the plain lovastatin powder.Thermodynamic stability studies also confirmed the stability of the prepared SMEDDS formulations.The optimized formulation,which consists of 12% of peceol,44% of cremophor RH 40,and 44% of transcutol-P was loaded into directly compressed liquid loadable tablet of Neusilin■ US2 by simple adsorption method.In order to determine the ability of Neusilin®US2 as a suitable carrier pharmacodynamics study were also carried out in healthy diet induced hyperlipidemic rabbits.Animals were administered with both liquid SMEDDS and solid SMEDDS as well.From the results obtained,Neusilin■ was found to be a suitable carrier for SMEDDS and was equally effective in reducing the elevated lipid profile.In conclusion,liquid loadable tablet(LLT)is predicted to be a promising technique to deliver a liquid formulation in solid state.
基金the Innovation Team and Talents Support Program of National Administration of Traditional Chinese Medicine:Construction and Practice of Pharmacovigilance Theory System in Line with the Characteristics of Traditional Chinese Medicine (No. ZYYCXTD-C-202005-11)the National Leading Talents Support Plan of Traditional Chinese Medicine 'Qihuang Scholar' Plan:Chinese Medicine Inheritance and Innovation "One Hundred Million" Talent Project (Qihuang Project) Qihuang Scholars (No. 1040063320004)。
文摘OBJECTIVE: To explore the pharmacodynamic effects and potential mechanisms of Shuangling extract against ulcerative colitis(UC). METHODS: The bioinformatics method was used to predict the active ingredients and action targets of Shuangling extract against UC in mice. And the biological experiments such as serum biochemical indexes and histopathological staining were used to verify the pharmacological effect and mechanism of Shuangling extract against UC in mice. RESULTS: The Shuangling extract reduced the levels of seruminterleukin-1β(IL-1β), tumor necrosis factor-α(TNF-N), interleukin-6(IL-6) and other inflammatory factors in UC mice and inhibited the inflammatory response. AKT Serine/threonine Kinase 1 and IL-6 may be the main targets of the anti-UC action of Shuangling extract, and the TNF signaling pathway, Forkhead box O signaling pathway and T-cell receptor signaling pathway may be the main signaling pathways. CONCLUSION: The Shuangling extract could inhibit the inflammatory response induced by UC and regulate intestinal immune function through multiple targets and multiple channels, which provided a new option and theoretical basis for anti-UC.
基金supported by National Natural Science Foundation of China(No.81373338).
文摘In the present study,we prepared nattokinase-loaded self-double-emulsifying drug delivery system(SDEDDS)and investigated its preliminary pharmacodynamics.The type and concentration of oil phase,inner aqueous phase and emulsifier were screened to prepare optimum nattokinase-loaded SDEDDS.Next,the optimum formulations were characterized based on microstructure,volume-weighted mean droplet size,self-emulsifying rate,yield,storage stability,in vitro release and in vivo pharmacodynamics studies.The water/oil/watermultiple emulsions exhibited typicalmultiple structure,with relatively small volumeweighted mean droplet size 6.0±0.7μm and high self-emulsifying ability(self-emulsifying time<2 min).Encapsulation of nattokinase was up to 86.8±8.2%.The cumulative release of nattokinase within 8 h was about 30%,exhibiting a sustained release effect.The pharmacodynamics study indicated that nattokinase-loaded SDEDDS could significantly prolong the whole blood clotting time in mouse and effectively improve the carrageenan-induced tail thrombosis compared with nattokinase solution.Moreover,we showed that SDEDDS could successfully self-emulsify into water/oil/water multiple emulsions upon dilution in dispersion medium with gentle stirring and effectively protect nattokinase activity in gastric environment.Our findings suggested that SDEDDS could be a promising strategy for peptide and protein drugs by oral administration.
基金supported by a Health and Medical Research Fund(HMRF),Hong Kong SAR(No.18170352,China)to Pang-Chui Shaw.
文摘The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design.In this study,we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-based design to target the PB1-binding interface on PA.Biological evaluation of these compounds through a viral yield reduction assay revealed that compounds 27 and 31 both had a low micromolar range of the half maximal effective concentration(EC_(50))values against A/WSN/33(H1N1)(8.03 mmol/L for 27;14.6 mmol/L for 31),while the most potent candidate 24 had an EC_(50) value of 690 nM.Compound 24 was effective against different influenza strains including a pandemic H1N1 strain and an influenza B strain.Mechanistic studies confirmed that compound 24 bound PA with a K_(d) which equals to 1.88 mmol/L and disrupted the binding of PB1 to PA.The compound also decreased the lung viral titre in mice.In summary,we have identified a potent anti-influenza candidate with potency comparable to existing drugs and is effective against different viral strains.The therapeutic options for influenza infection have been limited by the occurrence of antiviral resistance,owing to the high mutation rate of viral proteins targeted by available drugs.To alleviate the public health burden of this issue,novel anti-influenza drugs are desired.In this study,we present our discovery of a novel class of indazolecontaining compounds which exhibited favourable potency against both influenza A and B viruses.The EC_(50) of the most potent compounds were within low micromolar to nanomolar concentrations.Furthermore,we show that the mouse lung viral titre decreased due to treatment with compound 24.Thus our findings identify promising candidates for further development of anti-influenza drugs suitable for clinical use.
基金supported by the China Postdoctoral Science Foundation(2022M712153)The National Natural Science Foundation of China(22367007,82304384)+6 种基金The Fundamental Research Funds for Hainan University(KYQD(ZR)23002,China)Hainan Provincial Natural Science Foundation of China(824RC500)National-Local Joint Engineering Research Center for Innovative&Generic Chemical Drug,and Guizhou High-level Innovative Talents Supporting Program(2016-4015,China)The State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University(Grant number FAMP202107K,China)Guizhou Science and Technology Platform Talents(QKHRCPT[2019]5627,China)Program for Innovative Research Team in Universities of Inner Mongolia Autonomous Region(NMGIRT2216,China)Natural Science Foundation of Inner Mongolia Autonomous Region of China(2020MS08103).
文摘Alzheimer’s disease(AD)is a common neurodegenerative disorder among the elderly,and BuChE has emerged as a potential therapeutic target.In this study,we reported the development of compound 8e,a selective reversible BuChE inhibitor(eqBuChE IC_(50)=0.049 mmol/L,huBuChE IC_(50)=0.066 mmol/L),identified through extensive virtual screening and lead optimization.Compound 8e demonstrated favorable bloodebrain barrier permeability,good drug-likeness property and pronounced neuroprotective efficacy.Additionally,8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice.Further,8e significantly improved cognitive function in APP/PS1 transgenic mice.Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor(VLDLR),offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway.Thus,compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD,with significant implications for further exploration into its mechanisms of action and therapeutic applications.
