Felodipine对兔缺血心肌作用

通过兔心肌缺血模型，观察心肌缺血时多项生化指标、组织学变化及Ｆｅｌｏｄｉｐｉｎｅ对缺血性心肌的影响。结果：兔心肌缺血０．５ｈ时，心肌丙二醛、钙、中性粒细胞浸润数及组织含水量均明显升高，而超氧化物歧化酶、Ｎａ￣＋－Ｋ￣＋－ＡＴＰａｓｅ和Ｃａ￣（２＋），Ｍｇ￣（２＋）－ＡＴＰａｓｅ活性明显下降。用Ｆｅｌｏｄｉｐｉｎｅ治疗，上述改变明显减轻，心肌超微结构变化改善，且对心率、血压无明显影响。提示上述诸因素共同参与了心肌缺血性损伤，Ｆｅｌｏｄｉｐｉｎｅ对心肌损伤有明显的保护作用。

Felodipine对心肌缺血作用实验研究

Ｆｅｌｏｄｉｐｉｎｅ对心肌缺血作用实验研究司良毅，张远慧，赵学，王国超（重庆第三军医大学附一院心内科，６３００３８）钙拮抗剂对缺血心肌的作用已有诸多报道，但多为对单一致损因素的研究。本文观察了新型钙拮抗剂Ｆｅｌｏｄｉｐｉｎｅ（Ｆｅｌ）对缺血心肌钙、丙...

Sensitive and Rapid Quantification of Felodipine by High-performance Liquid Chromatography-tandem Mass Spectrometry(HPLC-MS/MS) and Its Pharmacokinetics in Healthy Chinese Volunteers

To investigate the pharmacokinetics of felodipine in the plasma of healthy Chinese volunteers, 30 healthy volunteers received a single oral dose of 5 mg of extended release felodipine tablets. The felodipine was extracted from the matrix with a liquid-liquid extract procedure and analyzed by high-performance liquid chromatography-tandem mass spectrometry in the multiple reaction monitoring（MRM） mode using an electrospray ion source with positive ion detection. The method was validated over a felodipine concentration range of 0. 05-10.00 ng/mL in human plasma. Its main pharmacokinetic parameters values were： ρmax = （ 1.67 ± 0. 84 ） ng/mL, occurring at （ 3.93 3± 2. 49 ） h; the plasma elimination half-life： （23. 08 3± 9. 48） h and the area under the plasma concentration versus time curve： （29. 94 ± 14. 39） ng · h/mL. The validation results demonstrated that this method showed a satisfactory precision and accuracy across the calibration range. The procedure involved minimal drug administration, sample preparation, and a 2. 5-min chromatographic run time. It was well suited to clinical studies of the drug involving large numbers of samples.

The influence of CYP3A5 ＊ 3 and BCRPC421A genetic polymorphisms on the pharmacokinetics of felodipine in healthy Chinese volunteers

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.

新型钙拮抗剂—氟罗地平(Felodipine)

氟罗地平,化学结构为4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5吡啶二羧酸甲乙酯,是一种新型的钙拮抗剂。药理学研究证实,氟罗地平与硝苯吡啶相比,其有选择性松驰血管平滑肌的作用,但对心肌无明显作用,是降血压和治疗心绞痛的有效药物。

Preparation and Evaluation of Molecularly Imprinted Monolithic Column for Felodipine in Micro-liquid Chromatography

This study concentrated on the production of molecularly imprinted polymers (MIPs) as highly selective sorbents for felodipine (FLD), a representive dihydropyridine calcium antagonists. Demonstrated chromatographically through a selection factor, these MIPs showed high selectivity for the template molecule among a group of structurally similar compounds. The recognition was found to correlate with structural similarity to the template compound.

Study of the Reactivity of (100) Felodipine Surface Model Based on DFT Concepts

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.

非洛地平 Felodipine

非洛地平(Felodipine)为Astra公司开发的第二代二氢吡啶类钙拮抗剂,具有选择性地舒张外周小动脉的高度活性;兼有减弱收缩力的作用。1988年在瑞典和丹麦上市。该药主要用于治疗高血压,缺铁性心脏病,且对心衰作用极佳。用于心绞痛的治疗研究目前尚在进行之中。可与β-阻滞剂或利尿药合用,或在认为其它抗高血压药治疗不适宜时单用。标准剂量为每日10mg,老人或轻度高血压患者,开始一般每天给以5mg,日剂量一般不超过20mg.缓释剂晨服一次,作用持续24h.

Enantioselective Conversion of Racemic Felodipine to S(-)-Felodipine by Aspergillus niger and Lipase AP6 Enzyme

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%).

Effect of felodipine in combined with irbesartan on the blood uric acid,serum adiponectin,and renal function in young males with essential hypertension

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.

Pharmacokinetics of two components in felodipine-enalapril sustained-release tablets in Chinese healthy volunteers

To compare the pharmacokinetics properties of enalapril-felodipine sustained-release tablet with enalapril and felodipine in the two reference formulations in Chinese healthy volunteers, the study was designed to a randomized, open label, crossover and two treatment pharmacokinetic study using enalapril-felodipine sustatined-release tablet as the test formulation. A total of 12 individuals were randomly assigned to 2 gorups （6 individuals in each group）. The wash-out period was 14 d. Compared with the reference formulations, felodipine in the sustained-release tablet showed significantly sustained-release characteristics, while the pharmacokinetics processes of enalapril and its active metabolite enalaprilat were basically similar in Chinese healthy volunteers.

Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus,persisters and biofilms

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.

Lercanidipine及其他钙离子阻断剂在高血压方面的使用

1882年Dr．Ringer发现肌肉收缩与体外钙离子浓度有关开始，科学家便想如果可以减少钙进入细胞，就应该能减少肌肉收缩。1962年Dr．AlbrechtFleckenstdn研究发展出第一个钙离子阻断剂-Verapamil，此后，陆陆继继有许多的华学分子被筛选为钙离子阻断剂，如1971年的Nffedipine，1973的Diltiazem。1982年verapamil正式临床许可应用子冠状动脉扩张。而nifedipine、diltiazem也陆续广泛的应用在治疗高血压和心绞痛。钙离子阻断剂大致可以分为dihydropyridinecalciumchannelblocker、benzothiazepines及chenylalkylamines。Nffedipine、diltiazem、verapamil目前仍是处方常用药，经由剂型的改良，发展出长效制剂以克服有效作用时间短和明显的副作用如心肌抑制作用、心跳加速、头痛、脸部潮红、足部水肿、昏睡、便秘等缺点。由nifedipine的结构衍生出的钙离子阻断剂，如felodipine、nimodipine等则是著重在加强心血管选择性，减少心肌抑制作用。但是仍然存在有效作用时间短和作用太快而易导致副作用的缺点。Lercanidipine是属于第三代dihydropyridine类的钙离子阻断剂，由于化学结构上带有巨大的bis-phenylalkylamine侧链，使午lercanidipine比amlodipine,nitrendipine、rimodipme脂溶性更强，能够快速的离开血中蛋自而溶入血管平滑肌的细胞膜中，藉著缓慢作用在细胞膜的L型钙离子通道，让细胞外钙离子无法进入细胞内。

High performance liquid chromatographic separation of eight drugs collected in Chinese Pharmacopoeia 2010 on amylose ramification chiral stationary phase

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.