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
OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(...OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(PD)and PK responses to clopidogrel should be effective for identifying the genetic variants affecting the antiplatelet response to the drug.METHODS A genome-wide association study was conducted to identify new genetic loci that modify PD responses to clopidogrel and its active metabolite H4 in 115 Chinese patients with coronary heart disease(CHD).RESULTS We identified novel variants in two transporter genes(rs12456693 in SLC14A2 and rs2487032 in ABCA1)and in N6AMT1(rs2254638)associated with clopidogrel-treated P2Y12reaction unit(PRU)and plasma H4 concentration.The associations between these single nucleotide polymorphisms(SNPs)and PK parameters of clopidogrel and H4 were observed in 31 additional CHD patients(P<0.05).The new variants,together with CYP2C19*2 and clinical factors,dramatically improved the predictability of PRU variability to 37.7%compared with the published value of approximately 20%.The function of these SNPs on the activation of clopidogrel was validated in 32 liver S9 fractions,and the N6AMT1 rs2254638 T variant was found to be associated with decreased formation of H4(P=0.0386).Meanwhile,N6AMT1 rs2254638 was further identified to exert a marginal risk effect for MACE in an independent CHD patient cohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).In conclusion,we systematically identified new genetic variants as risk factors for the reduced efficacy of clopidogrel.CONCLUSION Our study findings enhanced the understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.展开更多
Aim Clopidogrel therapy is associated with a substantial variability in pharmacokinetics （PK） and pharmacodynamics （PD） responses. To date, known gene variants explain only a small proportion of the variabili- ty....Aim Clopidogrel therapy is associated with a substantial variability in pharmacokinetics （PK） and pharmacodynamics （PD） responses. To date, known gene variants explain only a small proportion of the variabili- ty. A genome-wide association study （GWAS） was conducted to identify new genetic loci modifying PD responses to clopidogrel in Chinese patients with coronary heart disease （CHD）. The initial GWAS by combination analysis of PIL/PD included 115 patients with CHD. The PK validation included 31 patients with CHD and the metabolizing functional validation included 32 human liver tissues. We identified novel variants in two transporter genes （ rs12456693 in SLC14A2 and kgpl 1138762 in ABCA1 ） and in N6AMT1 （rs2254638） associated with not only clo- pidogrel on-treated P2Y12 reaction unit （PRU） （P 〈 1 × 10^-4） , but also plasma clopidogrel active metabolite H4 concentration （P 〈 1 × 10^-2）. The significant association between rs12456693, kgpl 1138762, or rs2254638 and PK parameters of clopidogrel （P 〈 1 × 10^-2） was observed in additional CHD patients. Further, the N6AMT1 rs2254638 T variant was found to be associated decreased activation of clopidogrel （P -3.86 × 10^-2）. The new variants in N6AMT1 and ABCA1, together with CYP2C19 ＊ 2, dramatically improve the predictability of PRU varia- bility to 37.7% compared with the published value of approximately 20%. The present study identifies novel genet- ic loci modifying PIL/PD responses to clopidogrel, which contributes to a better understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.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
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.
基金The project supported by National Natural Science Foundation of China(81373486)Science and Technology Development Projects of Guangdong Province,China(2016B090918114,2013B021800157)Science and Technology Development Projects of Guangzhou,Guangdong,China(201510010236,201604020096)
文摘OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(PD)and PK responses to clopidogrel should be effective for identifying the genetic variants affecting the antiplatelet response to the drug.METHODS A genome-wide association study was conducted to identify new genetic loci that modify PD responses to clopidogrel and its active metabolite H4 in 115 Chinese patients with coronary heart disease(CHD).RESULTS We identified novel variants in two transporter genes(rs12456693 in SLC14A2 and rs2487032 in ABCA1)and in N6AMT1(rs2254638)associated with clopidogrel-treated P2Y12reaction unit(PRU)and plasma H4 concentration.The associations between these single nucleotide polymorphisms(SNPs)and PK parameters of clopidogrel and H4 were observed in 31 additional CHD patients(P<0.05).The new variants,together with CYP2C19*2 and clinical factors,dramatically improved the predictability of PRU variability to 37.7%compared with the published value of approximately 20%.The function of these SNPs on the activation of clopidogrel was validated in 32 liver S9 fractions,and the N6AMT1 rs2254638 T variant was found to be associated with decreased formation of H4(P=0.0386).Meanwhile,N6AMT1 rs2254638 was further identified to exert a marginal risk effect for MACE in an independent CHD patient cohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).In conclusion,we systematically identified new genetic variants as risk factors for the reduced efficacy of clopidogrel.CONCLUSION Our study findings enhanced the understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.
文摘Aim Clopidogrel therapy is associated with a substantial variability in pharmacokinetics （PK） and pharmacodynamics （PD） responses. To date, known gene variants explain only a small proportion of the variabili- ty. A genome-wide association study （GWAS） was conducted to identify new genetic loci modifying PD responses to clopidogrel in Chinese patients with coronary heart disease （CHD）. The initial GWAS by combination analysis of PIL/PD included 115 patients with CHD. The PK validation included 31 patients with CHD and the metabolizing functional validation included 32 human liver tissues. We identified novel variants in two transporter genes （ rs12456693 in SLC14A2 and kgpl 1138762 in ABCA1 ） and in N6AMT1 （rs2254638） associated with not only clo- pidogrel on-treated P2Y12 reaction unit （PRU） （P 〈 1 × 10^-4） , but also plasma clopidogrel active metabolite H4 concentration （P 〈 1 × 10^-2）. The significant association between rs12456693, kgpl 1138762, or rs2254638 and PK parameters of clopidogrel （P 〈 1 × 10^-2） was observed in additional CHD patients. Further, the N6AMT1 rs2254638 T variant was found to be associated decreased activation of clopidogrel （P -3.86 × 10^-2）. The new variants in N6AMT1 and ABCA1, together with CYP2C19 ＊ 2, dramatically improve the predictability of PRU varia- bility to 37.7% compared with the published value of approximately 20%. The present study identifies novel genet- ic loci modifying PIL/PD responses to clopidogrel, which contributes to a better understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.
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.
