Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers

AIM: To study the influence of inducers of drug metabolism enzyme, beta-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes. METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots. Propafenone enantiomer concentrations were assayed by a chiral HPLC. RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubation of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R(-) isomer was observed in metabolism at low substrate concentrations of racemic propafenone, but lost the stereoselectivity at high substrate concentrations. However, in control group, no stereoselectivity was observed. The enzyme kinetic parameters were: (1) K(m). Control group: R(-) 83+/-6, S(+) 94+/-7; BNF group: R(-) 105+/-6, S(+)128+/-14; DEX group: R(-) 86+/-11, S(+) 118+/-16; (2)V(max). Control group: R(-) 0.75+/-0.16, S(+) 0.72+/-0.07; BNF group: R(-) 1.04+/-0.15, S(+)1.07+/-14; DEX group: R(-) 0.93+/-0.06, S(+) 1.04+/-0.09; (3)Cl(int). Control group: R(-) 8.9+/-1.1, S(+) 7.6+/-0.7; BNF group: R(-) 9.9+/-0.9, S(+)8.3+/-0.7; DEX group: R(-) 10.9+/-0.8, S(+) 8.9+/-0.9. The enantiomeric differences in K(m) and Cl(int) were both significant, but not in V(max), in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group. Furthermore, K(m) and V(max) were both significantly less than those in BNF or DEX group. In the rat liver microsome induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at low substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereoselective with R(-)-isomer being impaired more than S(+)-isomer. The inhibition constant (Ki) of S(+)- and R(-)-propafenone, calculated from Dixon plots, was 15.4 and 8.6 mg x L(-1), respectively. CONCLUSION: CYP1A subfamily(induced by BNF) and CYP3A4 (induced by DEX) have pronounced contribution to propafenone N-desalkylation which exhibited stereoselectivity depending on substrate concentration. The molecular base for this phenomenon is the stereoselectivity in affinity of substrate to the enzyme activity centers instead of at the catalyzing sites.

Enantioselective assay of S(+)- and R(-)-propafenone in human urine by using RP-HPLC with pre-column chiral derivatization

The enantioselective assay for S(+)- and R(-)-propafenone (PPF) in human urine that developed in this work involves extraction of propafenone from human urine and using S(+)-propafenone as internal standard, chiral derivatization with 2,3,4,6-tetra-O-b-D-glucopranosyl isothiocyanate, and quantitation by an RP-HPLC system with UV detection (l=220 nm). A baseline separation of propafenone enantiomers was achieved on a 5-mm reverse phase ODS column, with a mixture of methanol:water:glacial acetic acid (25:12:0.02,v/v) as mobile phase. There was good linear relationship from 24.9 ng/ml to 1875.0 ng/ml for both of enantiomers. The regression equations of the standard curves based on CS-PPF (or CR-PPF ) versus ratio of AS-PPF/AS (or AR-PPF/AS ) were y=0.0032x-0.081, (r=0.999) for S-PPF and y=0.0033x+0.0039, (r=0.998) for R-PPF, respectively. The method抯 limit of detection was 12.5 ng/ml for both enantiomers, and the method抯 limit of quantitation was 28.20.52 ng/ml for S-PPF, 30.40.53 ng/ml for R-PPF (RSD<8%, n=5). The analytical method yielded average recovery of 98.9% and 100.4% for S-PPF and R-PPF, respectively. The relative standard deviation was no more than 6.11% and 6.22% for S-PPF and R-PPF, respectively. The method enabled study of metabolism of S(+)- and R(-)-propafenone in human urine. The results from 7 volunteers administered 150 mg racemic propafenone indicated that propafenone enantiomers undergo stereoselective metabolism and that in the human body, S(+)-propafenone is metabolized more extensively than R(-)- propafenone.

Selective killing effect of oxytetracycline,propafenone and metamizole on A549 or Hela cells

Objective： To determine the selective killing effect of oxytetracycline, propafenone and metamizole on A549 or Hela cells. Methods： Proliferation assay, lactate dehydrogenase （LDH） assay, apoptosis detecting, flow cytometry and western blot were performed. Results： It was found that treatment with propafenone at the concentration of 0.014 g/L or higher for 48 h could induce apoptosis in Hela cells greatly, while it was not observed in oxytetracycline and metamizole at the concentration of 0.20 g/L for 48 h. Oxytetracycline, propafenone and metamizole all displayed evident inhibitory effects on the proliferation of A549 cells. The results of LDH assay demonstrated that the drugs at the test range of concentration did not cause necrosis in the cells. Propafenone could elevate the protein level of P53 effectively （P〈0.01）. Conclusions： Oxytetracycline, propafenone and metamizol （dipyrone） all displayed evident inhibitory effects on the proliferation of A549 cells. Propafenone also displayed evident inhibitory effects on the proliferation of Hela cells.

Electrophysiologic Effects of Propafenone on Action Potential of Neonatal and Adult Purkinje Fibers

The electrophysiological effects of 5.8×10-6 mol/L propafenonewere studied in neonatal canine Purkinje fiber compared with changes in theadult canine. The method used was microelectrode technique. This study sug-gests that Purkinje fibers are less sensitive to propafenone in the neonate than inthe adult, but at shorter ample lengths, the difference between them is not sig-nificant.

Effects of Isoproterenol and Metoprolol on the Suppression of Propafenone on with Supraventricular Tachycardia

This study was to determine whether isoproterenol (Iso) reverses the effects of propafenone(Pro) on the induction of supraventricular tarhycardia and whether the revergal during electrophysiologicstudy (EPS) is predictive of clinical recurrences of SVT during long-term treatment with Pro.Thirtypatients with inducible sustained SVT at baseline state were studied. Iso infusion at a rate necessary toachieve a 20%-40% increase in heart rate completely (16/28 cases,57%) or partially (5/28 case, 18%)revereed Pro's suppressant effects on the induction of SVT.There were clinical recurrcnces of SVT in fiveof 16 patients (31%) treated on a long-term basis (mean 4.5±3.6 months) with Pro,Iso completelyreveroed Pro's supprosant effect on the induction of SVT in four of these five patients (80%).These fivepatients then were treated with Pro and metoprolol and no further clincal recnrrences of SVT.These resultssuggested that reveroal by Iso ofpro's suppresaant effects on the induction of SVT may identify patients whoare likely to experience clinical recurrence of SVT and these patients may benefit from treatment with aB-blocker during longterm therapy with Pro.

Electrophysiologic Effects of Propafenone on Ischemic Ventricular Tachyarrhythmias

Objectives To observe the electrophysiologic effects of propafenone （Prop） on ischemic ventricular tachyarrhythmias. Methods A canine ischemic ventricular tachyarrhythmia model was established in open-chest dogs subjected to programmed electrical stimulation （PES） on 5-8 days after acute myocardial infarction. The electrophysiologic effects of propafenone were observed in the model. Results Propafenone distinctly lengthened the QTc interval （P 〉 0.01） and effective refractory period （ERP） of normal and ischemic ventricular myocardium （NERP and IERP） respectively （P 〉 0.01）, decreased the dispersion of ERP in ischemic myocardium and in left ventricle （P 〉 0.01）, and increased the diastolic excitability threshold of normal and ischemic ventricular myoeardium remarkably （P 〉 0.01）. Propafenone effectively prevented PES-induced ventricular tachycardia （VT） or ventricular fibrillation （VF） （P 〉 0.01） and ischemia-induced VT/VF （P 〉 0.05）. Conclusions The results indicated that the canine model produced by our methods is a worthy and reliable one, propafenone may be effective in preventing the onset of VT / VF after myocardial ischemic damage in dogs, and deserve further attention as an antifibrillatory agent.

Pharmacokinetics of propafenone hydrochloride sustained-release capsules in male beagle dogs

Ins paper describes the development and validation of a liquid chromatography mass spectrometric assay for propafenone and its application to a pharmacokinetic study of propafenone administered as a new propafenone hydrochloride sustained-release capsule (SR-test), as an instant-release tablet (IR-reference) and as the market leader sustained-release capsule (Rythmod SR-reference) in male beagle dogs (n= 8). In Study A comparing SR-test with IR-reference in a crossover design T-max and t(1/2) of propafenone for SR-test were significantly higher than those for IR-reference while C-max and AUC were lower demonstrating the sustained release properties of the new formulation. In Study B comparing SR-test with SR-reference the observed C and A TIC of propafenone for SR test (124.5 +/- 140.0 ng/mL and 612.0 +/- 699.2 ng.h/mL, respectively) were higher than for SR-reference (78.52 +/- 72.92 ng/mL and 423.6 +/- 431.6 ng.h/mL, respectively) although the differences were not significant. Overall, the new formulation has as good if not better sustained release characteristics to the market leader formulation. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier By All rights reserved.

普罗帕酮诱发Brugada样心电图改变一例

Brugada综合征主要在成年时期出现症状,且主要在休息或睡眠中发生猝死,儿童时期并不常见,尤其以心房扑动为首发表现的相关报道鲜见。本文报道一例以心房扑动为首发表现的13岁患儿,无基础心脏疾病,在接受普罗帕酮治疗的过程中诱发出Brugada样心电图改变,基因检测发现可疑变异基因SCN5A,变异位点为c.2834A>G(p.D945G)。希望通过本病例的诊断、治疗及相关文献回顾,提高临床医师对Brugada综合征的诱发因素以及其可合并多种心律失常的认识,加强在应用抗心律失常药物时的心电监测,并对此类高危人群进行指导和密切随访,从而避免不良事件的发生。

普罗帕酮致严重便秘1例报道

普罗帕酮的不良反应临床研究多忽视胃肠道反应,未见致严重便秘或混合痔嵌顿不良事件的报道。现报道1例心律失常病例,患者3次应用盐酸普罗帕酮片,反复出现便秘症状,降低用量后无效,停药后未再发生。根据患者的临床表现及用药时间的关联性,考虑是盐酸普罗帕酮片导致的严重便秘、混合痔嵌顿。提示临床应用盐酸普罗帕酮片应当按照说明书要求从小剂量开始治疗,并告知患者可能存在的不良反应,如仍出现不良反应并无法耐受,及时停药或加用中医药治疗,以此提出该药的用药警戒。

盐酸胺碘酮注射液结合盐酸普罗帕酮注射液对急诊阵发性室上性心动过速患者血压、心功能指标的影响

目的探讨在急诊阵发性室上性心动过速(paroxysmal supraventricular tachycardia,PSVT)患者中应用盐酸胺碘酮注射液结合盐酸普罗帕酮注射液治疗的具体影响。方法回顾性选取淄博昌国医院于2020年4月—2023年8月收治的80例急诊PSVT患者的临床资料,按照治疗方法将患者分为观察组、对照组。对照组(40例)皮下注射盐酸普罗帕酮注射液,观察组(40例)在对照组基础上皮下注射盐酸胺碘酮注射液。比较两组的临床疗效、血压水平、心功能指标、不良反应发生情况。结果观察组治疗总有效率为92.50%(37/40),高于对照组的75.00%(30/40),差异有统计学意义(χ^(2)=4.501,P<0.05);治疗后观察组收缩压、左室收缩末期容积、舒张压、左室舒张末期内径、左室舒张末期容积均较对照组低,左心室射血分数较对照组高,差异有统计学意义(P均<0.05);两组的不良反应发生情况比较,差异无统计学意义(P>0.05)。结论盐酸胺碘酮注射液结合盐酸普罗帕酮注射液用于PSVT患者,具有明显治疗效果,可对患者血压进行有效调节,改善心功能水平,且用药安全性高。

观察普罗帕酮与胺碘酮治疗混合性心律失常的临床疗效

目的 观察普罗帕酮与胺碘酮治疗混合性心律失常的临床疗效。方法 272例混合性心律失常患者,根据随机数字表法分为对照组与观察组,每组136例。对照组实施胺碘酮治疗,观察组实施普罗帕酮+胺碘酮治疗。对比两组的临床疗效、心功能指标[左心室舒张末期内径(LVEDD)、左心室收缩末期内径(LVESD)、左心室射血分数(LVEF)、心输出量(CO)、6 min步行距离]、血清炎症因子[白细胞介素-6(IL-6)、超敏C反应蛋白(hs-CRP)]水平、不良反应发生情况。结果 观察组治疗总有效率为95.59%,明显高于对照组的82.35%(P<0.05)。治疗后,观察组LVEDD(56.82±6.12)mm、LVESD(43.36±5.60)mm均明显小于对照组的(61.25±6.33)、(48.22±5.47)mm,LVEF(55.14±5.47)%、CO(4.75±0.48)L/min均明显高于对照组的(50.02±5.33)%、(4.10±0.45)L/min,6 min步行距离(530.11±38.59)m明显长于对照组的(422.96±31.56)m(P<0.05)。治疗后,观察组hs-CRP、IL-6水平分别为(8.15±2.16)mg/L、(18.96±1.96)pg/ml,均明显低于对照组的(12.23±3.25)mg/L、(23.10±2.03)pg/ml(P<0.05)。两组不良反应发生率对比无明显差异(P>0.05)。结论 对于混合性心律失常患者而言,普罗帕酮联合胺碘酮的临床疗效显著,利于心功能的改善及缓解炎性反应,值得临床采纳并推广。

盐酸普罗帕酮片和胺碘酮治疗心律失常的临床效果及对心功能的影响

目的探讨盐酸普罗帕酮片和胺碘酮治疗心律失常的应用效果及对患者心功能的影响。方法选取2021年1月—2023年10月福建医科大学附属漳州市医院心血管内科收治的108例心律失常患者,以随机数字表法分为对照组与观察组,各54例。对照组予以盐酸普罗帕酮片治疗,观察组予以胺碘酮治疗。探讨其应用效果。结果观察组总有效率为100%,高于对照组的87.04%,差异有统计学意义(P<0.05)。治疗后,2组左室射血分数(left ventricular ejection fraction,LVEF)高于治疗前,左室收缩末期内径(left ventricular end-systolic diameter,LVESD)、左室舒张末期内径(left ventricular end-diastolic diameter,LVEDD)低于治疗前,差异有统计学意义(P<0.05);观察组LVEF为(53.02±2.12)%,高于对照组的(44.85±1.62)%;观察组LVEDD、LVESD分别为(42.52±2.11)mm、(35.96±1.26)mm,低于对照组的(54.11±2.35)mm、(43.11±1.44)mm,差异有统计学意义(P<0.05)。2组室性期前收缩、房性期前收缩、房室交界性期前收缩低于治疗前,差异有统计学意义(P<0.05);观察组室性期前收缩、房性期前收缩、房室交界性期前收缩低于对照组,差异有统计学意义(P<0.05)。2组生理功能、社会功能、情感职能、精神健康评分高于治疗前,差异有统计学意义(P<0.05);观察组生理功能、社会功能、情感职能、精神健康评分高于对照组,差异有统计学意义(P<0.05)。观察组总满意度为98.15%,高于对照组的83.33%,差异有统计学意义(P<0.05)。结论在心律失常治疗上选择胺碘酮的应用效果较盐酸普罗帕酮片更优,其不仅可改善患者的心功能指标和心律失常指标,提升其生活各项评分和治疗满意度,改善预后。

胺碘酮与普罗帕酮对快速心律失常患者治疗效果比较

目的:对比胺碘酮与普罗帕酮对快速心律失常患者的治疗效果。方法:选取2021年12月—2023年12月临沂市中心医院急诊科收治的102例快速心律失常患者为研究对象,按随机数字表法将其分为试验组和对照组,各51例。对照组采用普罗帕酮治疗,试验组采用胺碘酮治疗。比较两组患者的治疗效果、心功能指标及不良反应发生情况。结果:试验组治疗总有效率为92.16%,高于对照组的76.47%,差异有统计学意义(P<0.05)。治疗后,试验组左心室射血分数高于对照组,心排血量、舒张晚期峰值(A峰)流速均快于对照组、舒张晚期峰值(E峰)流速慢于对照组,E/A水平低于对照组,差异均有统计学意义(P<0.05)。试验组不良反应发生率为3.92%,低于对照组的15.69%,差异有统计学意义(P<0.05)。结论:相比于普罗帕酮,胺碘酮对快速心律失常患者的治疗效果更显著,能够有效改善患者心功能指标,控制患者病情,且临床不良反应较少。

普罗帕酮联合前列地尔治疗心衰合并快速心律失常的效果

目的探讨普罗帕酮联合前列地尔治疗心衰合并快速心律失常的疗效。方法选取2021年9月至2023年8月我院收治的100例心衰合并快速心律失常患者,按照抽签法分为两组。对照组采用前列地尔治疗,观察组采用普罗帕酮联合前列地尔治疗。比较两组的心律失常事件、血清指标、心功能指标。结果治疗后,观察组房性早搏、室性早搏、短阵室速数量及BNP、CRP水平均低于对照组,CI、LVEF高于对照组(P<0.05)。结论普罗帕酮联合前列地尔可控制心衰合并快速心律失常患者的症状,调节BNP及CRP水平,改善患者心功能。

体内普罗帕酮及其代谢物的GC-MS检验

In this paper,propafenone in judicial anatomy was quantitated and found to be 11.6 μg/mL in blood,17.8 μg/mL in urine,292 μg/g in gastric content and 196 μg/g in liver with GC-MS. Two metabolites from propafenone have been defined.In conclusion,as the dead body himself is a drug abuser and also his blood concentration of propafenone exceed the fatal dose,this case is finally identified to a death cause from the overdose of propanenone abuse.

尼非卡兰联合普罗帕酮对老年心律失常患者心率变异性及炎症反应的影响

目的 研究尼非卡兰联合普罗帕酮对老年心律失常患者心率变异性(heart rate variability,HRV)及炎症反应的影响。方法 选取80例老年心律失常患者为研究对象,根据治疗方案将其分为对照组和联合组,各40例。对照组采用普罗帕酮治疗,联合组采用尼非卡兰注射液联合普罗帕酮治疗。比较两组的临床疗效,以及治疗前后HRV指标(SDNN、SDANN、rMSSD、PNN50),血液流变学指标[纤维蛋白原(fibrinogen,Fib)、全血低切黏度(low shear rate blood viscosity,LBV)、血浆黏度(plasma viscosity,PV)、全血高切黏度(high shear rate blood viscosity,HBV)]、血清炎症相关因子[超敏C反应蛋白(hypersensitive C-reactive protein,hs-CRP)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、核因子κB(nuclear factorκB,NF-κB)、聚腺苷酸二磷酸核糖聚合酶1(polyadenylate diphosphoribose polymerase 1,PARP1)]水平和不良反应发生率。结果 联合组的临床总有效率高于对照组(95.00%vs.77.50%,P<0.05)。联合组治疗14 d后SDNN、SDANN、rMSSD、PNN50显著高于对照组(P<0.05),而Fib、LBV、PV、HBV水平显著低于对照组(P<0.05)。相较于对照组,联合组治疗14 d后血清PARP1、TNF-α、hs-CRP、NF-κB水平更低(P<0.05);两组间不良反应总发生率差异无统计学意义(P>0.05)。结论 采用尼非卡兰与普罗帕酮联合治疗可改善老年心律失常患者HRV及血液流变学,缓解炎症状态,改善疗效,且安全性良好。

胺碘酮与普罗帕酮治疗心律失常的临床效果及安全性对比分析

目的探讨胺碘酮与普罗帕酮治疗心律失常的临床效果及安全性对比分析。方法将2022年1—12月在本院治疗的94例心律失常患者随机分为两组,对照组(47例)使用普罗帕酮治疗,观察组(47例)使用胺碘酮治疗,对比两组的临床疗效、心肌损伤标志物、心功能及CRP水平、不良反应。结果治疗有效率组间统计学结果显示,观察组明显更高,组间差异有统计学意义(P<0.05);观察组治疗后CK-MB、cTnI、BNP水平均低于对照组,组间差异有统计学意义(P<0.05);观察组治疗后LVEF明显高于对照组,HR、SBP、CRP均低于对照组,组间差异有统计学意义(P<0.05);观察组不良反应发生率低于对照组,组间差异有统计学意义(P<0.05)。结论胺碘酮治疗心律失常的临床效果及安全性更好,能有效改善心功能,减少心肌损伤,降低炎症反应程度,具有积极的临床意义。

氧化苦参碱对冠心病患者心律失常及心率变异性的影响

目的应用动态心电图和心率变异性指标评价氧化苦参碱对冠心病患者心律失常及心率变异性的影响。方法将冠心病频发心律失常患者110例随机分为氧化苦参碱组和普鲁帕酮组,每组各55例,用药前后分别记录48h动态心电图,评价患者一般状态、早搏次数,PR间期、RR间期及24h心率变异性指标的改变。结果用药后两组患者对房性和室性心律失常均有效(P<0.01),普鲁帕酮组减少房性早搏的效果比氧化苦参碱组更明显(P<0.05),两组减少室性早搏的效果比较差异无显著性(P>0.05),两组治疗后心率变异性各参数较治疗前均显著升高(P<0.01),两组治疗后比较差异有显著性(P<0.05)。结论氧化苦参碱可以显著提高冠心病心律失常患者心率变异性,对于房性和室性心律失常均有显著疗效。

心律平与胺碘酮治疗心律失常疗效比较的Meta分析

目的评价文献中运用心律平与胺碘酮治疗心律失常的疗效。方法运用计算机检索Pubmed、EMbase、Cochrane图书馆、中国生物医学文献数据库中关于心律平和胺碘酮在治疗心律失常疗效的随机对照试验,将检索时限定为2000年1月~2014年7月。对检索到的论文进行客观质量评价,应用Cochrane协作网提供的Rev Man 5.3软件进行Meta分析。结果通过药物静脉注射给药,2组心律失常总有效率差异有统计学意义(OR=1.68,95%CI:1.25~2.26,P<0.0001);药物口服给药,2组心律失常总有效率差异有统计学意义(OR=1.49,95%CI:1.09~2.03,P=0.010);2组不良反应发生率比较差异无统计学意义(OR=0.85,95%CI:0.62~1.16,P>0.05)。结论胺碘酮组治疗心率失常的疗效优于心律平,但对于药物的不良反应率并不增加。

治疗老年快速室上性心律失常的药物选择和疗效观察

目的观察静脉注射胺碘酮、普罗帕酮、地尔硫艹卓维拉帕米对老年快速室上性心律失常的疗效和安全性。方法对127例快速室上性心律失常的老年患者,根据全身状况和基础病变,采用个体化用药原则,分别给予上述四种药物。结果四种药物对室上性心动过速、心房纤颤、心房扑动治疗的总有效率均在80%以上,其中地尔硫艹卓、维拉帕米对室上性心动过速总有效率分别为91%和92%。结论只要掌握好个体化用药原则,上述四种抗心律失常药物,均可安全有效地用于治疗老年快速室上性心律失常。