Aim The aim of this study was to evaluate the pharmacogenetic variability in the disposition of felodip- ine in healthy Chinese subjects. Methods A single oral dose of 5 mg felodipine was orally administered to 45 hea...Aim The aim of this study was to evaluate the pharmacogenetic variability in the disposition of felodip- ine in healthy Chinese subjects. Methods A single oral dose of 5 mg felodipine was orally administered to 45 healthy Chinese subjects. The serum concentrations of felodipine were measured by using LC/MS/MS. We detected the SNPs of CYP450 enzymes and transporters, which play vital roles in drug metabolism and are with a high fre- quency of mutation in Chinese. Results The area under the plasma concentration - time curve （AUC） within the time points 0 to 72 h （AUC（0-72） ） after felodipine administration was significantly higher in the subjects possessing the CYP3A5 ＊ 1/＊ 3 alleles than in those with the CYP3A5 ＊ 1/＊ 1 alleles （P =0. 021 ）. The BCRP 421A allele was associated with a trend of reduced pharmacokinetic exposure （P = 0. 034）. The mean Tmax in subjects with the CYP3A4 ＊ 1/＊ 18B carriers was longer than in those with the CYP3A4 ＊ 1/＊ 1. The pharmacokinetics charac- teristics of felodipine were not associated with other SNPs we investigated. Conclusion This study showed that the genetic polymorphisms of CYP3A5＊ 3 and BCRPC421A might explain the variability in the pharmacokinetics of felodipine in the Chinese population.展开更多
In this study, Density Functional Theory including a dispersion correction is employed to model and analyze the structural, electronic and local reactivity of the (100) surface of felodipine. The surface energy calcul...In this study, Density Functional Theory including a dispersion correction is employed to model and analyze the structural, electronic and local reactivity of the (100) surface of felodipine. The surface energy calculated at the Generalized Gradient Approximation (GGA) level, along with plane waves as basis set and ultrasoft pseudopotentials, shows that the (100) surface is the most stable as compared to the (010) and (110) ones. In particular, we have focused on performing a quantitative study of the reactivity of the surface by means of the Fukui function and through the HOMO and LUMO populations. Our results can be related to some applications in the pharmaceutical chemistry of this compound.展开更多
The present study involves the enantioselective resolution of racemic Felodipine by using free and immobilized forms of microbial cultures as well as an enzyme (Lipase AP6). Among the microbial cultures employed in th...The present study involves the enantioselective resolution of racemic Felodipine by using free and immobilized forms of microbial cultures as well as an enzyme (Lipase AP6). Among the microbial cultures employed in the present study, Aspergillus niger, Sphingomonas paucimobilis, Cunninghamella elegans, Escherichia coli, Pseudomonas putida and Cunninghamella blakesleeana were found to possess capability of enantioselective resolution of racemic Felodipine. The enantiomeric excess (ee%) of Felodipine after reaction catalyzed by whole-cell A. niger and S. paucimobilis was found as 81.59 and 71.67%, respectively. Immobilization enhanced the enantioselectivity (enantiomeric ratio (E)) of the biocatalysts and hence this led to enhanced enantiomeric purity of the drug. The ee% values were found to be enhanced in reactions catalyzed by A. niger and S. paucimobilis cultures after immobilization as 98.27 and 93.56%, respectively. Enantiomeric ratio (E) of the reactions catalyzed by all the biocatalysts has been improved after immobilization. E value of the reaction catalyzed by immobilized A. niger was found to be excellent (E > 100) and hence the drug showed high enantiomeric purity. In lipase AP6 catalyzed study, the enantioselectivity was enhanced after immobilization with excellent E value, which led to enhanced enantiomeric purity of the drug (99.21% ee%).展开更多
Objective: To explore the effect of felodipine in combined with irbesartan on the blood uric acid (UA);serum adiponectin (APN);and renal function in young males with essential hypertension (EH). Methods: A total of 13...Objective: To explore the effect of felodipine in combined with irbesartan on the blood uric acid (UA);serum adiponectin (APN);and renal function in young males with essential hypertension (EH). Methods: A total of 134 young male patients with EH who were admitted in our hospital from January;2016 to January;2017 were included in the study and randomized into the observation group and the control group. The patients in the control group were given felodipine sustanined release tablets;5 mg/time;1 time/d. On this basis;the patients in the observation group were given irbesartan;150 mg/time;1 time/d. To those whose blood pressure was not reduced under 140/90 mmHg after 4 week treatment;the dose of felodipine sustanined release tablets was increased to 10 mg/d. A maintenance dose was adopted according to the individual conditions until the ideal blood pressure reduction effect was achieved. The morning fasting venous blood was collected before treatment;4 and 12 weeks after treatment in the two groups. ELISA was used to detect APN level. Uricase-peroxide enzymic method was used to detect UA level. The full automatic biochemical analyzer was used to detect BUN and Scr. Ccr was calculated. Urine was collected. RIA was used to detect 24 h Upro. The morning fasting venous blood before treatment;24 and 48 weeks after treatment was collected. RIA was used to detect the serum T and SHBG levels. Results: Scr and 24 h Upro 4 and 12 weeks after treatment in the two groups were gradually reduced;while Ccr was gradually elevated. BUN 12 weeks after treatment in the observation group was significantly reduced. Scr and 24 h Upro 4 and 12 weeks after treatment in the observation group were significantly lower than those in the control group;while Ccr was significantly higher than that in the control group. BUNS 12 weeks after treatment in the observation group were significantly lower than those in the control group. T level 24 and 48 weeks after treatment in the two groups was significantly elevated;while SHBG after treatment was not significantly changed. T level 24 and 48 weeks after treatment in the observation group was significantly higher than that in the control group. APN 4 and 12 weeks after treatment in the two groups was significantly elevated;while UA was significantly reduced. APN 4 and 12 weeks after treatment in the observation group was significantly higher than that in the control group;while UA was significantly lower than that in the control group. Conclusions: Felodipine in combined with irbesartan in the treatment of EH in young males can effectively regulate APN and UA levels;protect the renal function;enhance the sex hormone levels;and has a great significance in reducing the target organ damage and improving the prognosis.展开更多
Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chron...Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chronic implant infections in clinical,only few drugs are effective in clearing persisters and formed biofilms.Here,felodipine,a dihydropyridine calcium channel blocker,was reported for the first time to have antibacterial effects against MRSA,biofilm,and persisters.Even after continuous exposure to sub-lethal concentrations of felodipine,bacteria are less likely to develop resistance.Besides,low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance(aacA-aphD).Next,biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters.Furthermore,the result of protein profiling,and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence(agrABC),biofilm formation and TCA cycle.Then,molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease,which could lead to substantial protein degradation.Furthermore,murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response.In conclusion,low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA,biofilm,and persisters.展开更多
The enantiomers separation of ei ght pharmaceutical racemates collected in Chinese Pharmacopoeia 2010(Ch.P2010),including nitrendipine,felodipine,omeprazole,praziquantel,sulpiride,clenbuterol hydrochloride,verapamil h...The enantiomers separation of ei ght pharmaceutical racemates collected in Chinese Pharmacopoeia 2010(Ch.P2010),including nitrendipine,felodipine,omeprazole,praziquantel,sulpiride,clenbuterol hydrochloride,verapamil hydrochloride and chlorphenamine maleate,was performed on chiral stationary phase of amylose ramification by high performance liquid chromatography(HPLC)on Chiralpak AD-H column and Chiralpak AS-H column with the mobile phase consisted of isopropanol and n-hexane.The detection wavelength and the flow rate were set at 254 nm and 0.7 mL/min,respectively.The effects of proportion of organic additives,alcohol displacer and temperature on the separation were investigated.The results indicated that eight chiral drugs were separated on chiral stationary phase of amylase ramification in normal phase chroma tographic system.The chromatographic retention and resolution of enantiomers were adjusted by factors,including the changes of the concentration of alcohol displacer in mobile phase,organic alkaline modifier and column temperature.It was shown that the resolution was improved with reducing concentration of alcohol displacer.When the concentration of organic alkaline modifier was 0.2%,the resolution and the peak shape were fairly good.Most racemates mentioned above had the best resolution at column temperature of 25℃.The best temperature should be kept unchanged in the process of separation so as to obtain stable separation results.展开更多
文摘Aim The aim of this study was to evaluate the pharmacogenetic variability in the disposition of felodip- ine in healthy Chinese subjects. Methods A single oral dose of 5 mg felodipine was orally administered to 45 healthy Chinese subjects. The serum concentrations of felodipine were measured by using LC/MS/MS. We detected the SNPs of CYP450 enzymes and transporters, which play vital roles in drug metabolism and are with a high fre- quency of mutation in Chinese. Results The area under the plasma concentration - time curve （AUC） within the time points 0 to 72 h （AUC（0-72） ） after felodipine administration was significantly higher in the subjects possessing the CYP3A5 ＊ 1/＊ 3 alleles than in those with the CYP3A5 ＊ 1/＊ 1 alleles （P =0. 021 ）. The BCRP 421A allele was associated with a trend of reduced pharmacokinetic exposure （P = 0. 034）. The mean Tmax in subjects with the CYP3A4 ＊ 1/＊ 18B carriers was longer than in those with the CYP3A4 ＊ 1/＊ 1. The pharmacokinetics charac- teristics of felodipine were not associated with other SNPs we investigated. Conclusion This study showed that the genetic polymorphisms of CYP3A5＊ 3 and BCRPC421A might explain the variability in the pharmacokinetics of felodipine in the Chinese population.
文摘In this study, Density Functional Theory including a dispersion correction is employed to model and analyze the structural, electronic and local reactivity of the (100) surface of felodipine. The surface energy calculated at the Generalized Gradient Approximation (GGA) level, along with plane waves as basis set and ultrasoft pseudopotentials, shows that the (100) surface is the most stable as compared to the (010) and (110) ones. In particular, we have focused on performing a quantitative study of the reactivity of the surface by means of the Fukui function and through the HOMO and LUMO populations. Our results can be related to some applications in the pharmaceutical chemistry of this compound.
文摘The present study involves the enantioselective resolution of racemic Felodipine by using free and immobilized forms of microbial cultures as well as an enzyme (Lipase AP6). Among the microbial cultures employed in the present study, Aspergillus niger, Sphingomonas paucimobilis, Cunninghamella elegans, Escherichia coli, Pseudomonas putida and Cunninghamella blakesleeana were found to possess capability of enantioselective resolution of racemic Felodipine. The enantiomeric excess (ee%) of Felodipine after reaction catalyzed by whole-cell A. niger and S. paucimobilis was found as 81.59 and 71.67%, respectively. Immobilization enhanced the enantioselectivity (enantiomeric ratio (E)) of the biocatalysts and hence this led to enhanced enantiomeric purity of the drug. The ee% values were found to be enhanced in reactions catalyzed by A. niger and S. paucimobilis cultures after immobilization as 98.27 and 93.56%, respectively. Enantiomeric ratio (E) of the reactions catalyzed by all the biocatalysts has been improved after immobilization. E value of the reaction catalyzed by immobilized A. niger was found to be excellent (E > 100) and hence the drug showed high enantiomeric purity. In lipase AP6 catalyzed study, the enantioselectivity was enhanced after immobilization with excellent E value, which led to enhanced enantiomeric purity of the drug (99.21% ee%).
文摘Objective: To explore the effect of felodipine in combined with irbesartan on the blood uric acid (UA);serum adiponectin (APN);and renal function in young males with essential hypertension (EH). Methods: A total of 134 young male patients with EH who were admitted in our hospital from January;2016 to January;2017 were included in the study and randomized into the observation group and the control group. The patients in the control group were given felodipine sustanined release tablets;5 mg/time;1 time/d. On this basis;the patients in the observation group were given irbesartan;150 mg/time;1 time/d. To those whose blood pressure was not reduced under 140/90 mmHg after 4 week treatment;the dose of felodipine sustanined release tablets was increased to 10 mg/d. A maintenance dose was adopted according to the individual conditions until the ideal blood pressure reduction effect was achieved. The morning fasting venous blood was collected before treatment;4 and 12 weeks after treatment in the two groups. ELISA was used to detect APN level. Uricase-peroxide enzymic method was used to detect UA level. The full automatic biochemical analyzer was used to detect BUN and Scr. Ccr was calculated. Urine was collected. RIA was used to detect 24 h Upro. The morning fasting venous blood before treatment;24 and 48 weeks after treatment was collected. RIA was used to detect the serum T and SHBG levels. Results: Scr and 24 h Upro 4 and 12 weeks after treatment in the two groups were gradually reduced;while Ccr was gradually elevated. BUN 12 weeks after treatment in the observation group was significantly reduced. Scr and 24 h Upro 4 and 12 weeks after treatment in the observation group were significantly lower than those in the control group;while Ccr was significantly higher than that in the control group. BUNS 12 weeks after treatment in the observation group were significantly lower than those in the control group. T level 24 and 48 weeks after treatment in the two groups was significantly elevated;while SHBG after treatment was not significantly changed. T level 24 and 48 weeks after treatment in the observation group was significantly higher than that in the control group. APN 4 and 12 weeks after treatment in the two groups was significantly elevated;while UA was significantly reduced. APN 4 and 12 weeks after treatment in the observation group was significantly higher than that in the control group;while UA was significantly lower than that in the control group. Conclusions: Felodipine in combined with irbesartan in the treatment of EH in young males can effectively regulate APN and UA levels;protect the renal function;enhance the sex hormone levels;and has a great significance in reducing the target organ damage and improving the prognosis.
基金supported by the National Natural Science Foundation of China(Grant No.82172464,82172453,81972086)National Key Research and Development Project of China(Grant No.2020YFC1107500,2020YFC1107503)+4 种基金The Shanghai Rising-Star Program(21QA1405500)Shanghai“Rising Stars of Medical Talent”Youth Development Program(Youth Medical Talents-Specialist Program)(Grant No.2019-72)“Technology Innovation Action Plan”Key Project of Shanghai Science and Technology Commission(Grant No.19411962800)Shanghai municipal education commission-Gaofeng clinical medicine grant support(Grant No.20161423)NSFC Advancing Targeted Projects(RJTJ-JX-005,RJTJ22-RC-011).
文摘Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chronic implant infections in clinical,only few drugs are effective in clearing persisters and formed biofilms.Here,felodipine,a dihydropyridine calcium channel blocker,was reported for the first time to have antibacterial effects against MRSA,biofilm,and persisters.Even after continuous exposure to sub-lethal concentrations of felodipine,bacteria are less likely to develop resistance.Besides,low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance(aacA-aphD).Next,biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters.Furthermore,the result of protein profiling,and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence(agrABC),biofilm formation and TCA cycle.Then,molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease,which could lead to substantial protein degradation.Furthermore,murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response.In conclusion,low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA,biofilm,and persisters.
文摘The enantiomers separation of ei ght pharmaceutical racemates collected in Chinese Pharmacopoeia 2010(Ch.P2010),including nitrendipine,felodipine,omeprazole,praziquantel,sulpiride,clenbuterol hydrochloride,verapamil hydrochloride and chlorphenamine maleate,was performed on chiral stationary phase of amylose ramification by high performance liquid chromatography(HPLC)on Chiralpak AD-H column and Chiralpak AS-H column with the mobile phase consisted of isopropanol and n-hexane.The detection wavelength and the flow rate were set at 254 nm and 0.7 mL/min,respectively.The effects of proportion of organic additives,alcohol displacer and temperature on the separation were investigated.The results indicated that eight chiral drugs were separated on chiral stationary phase of amylase ramification in normal phase chroma tographic system.The chromatographic retention and resolution of enantiomers were adjusted by factors,including the changes of the concentration of alcohol displacer in mobile phase,organic alkaline modifier and column temperature.It was shown that the resolution was improved with reducing concentration of alcohol displacer.When the concentration of organic alkaline modifier was 0.2%,the resolution and the peak shape were fairly good.Most racemates mentioned above had the best resolution at column temperature of 25℃.The best temperature should be kept unchanged in the process of separation so as to obtain stable separation results.
