单硝酸异山梨醇酯在不同时辰对心绞痛病人的血液动力学效应

单硝酸异山梨醇酯(Monosan)为硝酸异山梨酯经肝脏代谢后的活性有效成分,其半衰期长,生物利用度近100%。作者研究其药效学,观察心绞痛病人20例,男18例,女2例;平均年龄57.9岁,心功能～级。用药剂量20mg,每次用药间隔28h,服药时间:第1d7:00,第2d11:00,第3d15:00,第4d19:00,第5d23:00。服药前和服药后1.5,2,3,4h检查心率和血压,用血流体积描记法测定血液动力学主要参数,观察在不同时辰病人血液动力学变化,查明主要指标对该药最敏感的时辰,以确定最佳服药时间。研究结果表明,服药后周围血管扩张,外周阻力降低;心搏出量减少,血压下降,心率加快,心…     

让合理、安全用药知识(五十二) 走进千家万户

(接上期)四、抗心绞痛药2.单硝酸异山梨酯(5-单硝酸异山梨醇、5-单硝酸异山梨醇酯、5-单硝酸异山梨酯、长效心痛治、异乐定)新一代长效硝酸酯类抗心绞痛药,作用机制与硝酸甘油相同,但作用时间较长。临床用于:1.用于冠心病的长期治疗;预防劳累性心绞痛、变异型心绞痛及混合     

让合理、安全用药知识(五十二) 走进千家万户

正(接上期)四、抗心绞痛药2.单硝酸异山梨酯(5-单硝酸异山梨醇、5-单硝酸异山梨醇酯、5-单硝酸异山梨酯、长效心痛治、异乐定)新一代长效硝酸酯类抗心绞痛药,作用机制与硝酸甘油相同,但作用时间较长。临床用于:1.用于冠心病的长期治疗;预防劳累性心绞痛、变异型心绞痛及混合     

中国人口服5-单硝酸异山梨醇酯缓释片的药动学和不良反应探讨

目的 :研究健康中国人口服 5 单硝酸异山梨醇酯缓释片 (5 0mg)的药动学 ,并同时观察不良反应。 方法 :受试者口服单剂量 5 单硝酸异山梨醇酯缓释片 (5 0mg) ,气相色谱法测定血清中 5 单硝酸异山梨醇酯的浓度。结果 :5 单硝酸异山梨醇酯缓释片的AUC0 ∞ =(10 10 9± 16 47)ng·ml-1·h-1,Tmax=(4.7± 0 .5 )h ,Cmax=(784± 83)ng·ml-1,T1/2 =(8.4± 1.9)h ;5 单硝酸异山梨醇酯缓释片的不良反应发生率为 83.3% ,主要表现为头痛、头晕和嗜睡。结论 :中国人服用 5 单硝酸异山梨醇酯缓释片时应适当减小剂量。     

单硝酸异山梨酯治疗高血压急症临床观察

目的 探讨单硝酸异山梨酯治疗高血压急症的疗效和安全性。方法 应用单硝酸异山梨酯；注射液20mg加入250m1液体中，以80～160μg／min静滴维持，根据血压调节滴速治疗36例高血压急症患者。用心电、血压监测并记录用药前及用药后5、10、30、60、120min血压（BP）、心率（HR）、伴随症状及不良反应。结果 应用单硝酸异山梨酯后各时段BP较用药前均明显下降，差异有显著性，而HR则无明显变化。结论 单硝酸异山梨酯治疗高血压急症，疗效确切，不良反应少。     

硝异山梨醇的体内代谢及生物利用度

硝异山梨醇(消心痛,ISDN)是一种常用韵抗心绞痛药,在人体内大部分被代谢为异山梨醇-2-单硝酸酯(IS-2-MN)和异山梨醇-5-单硝酸酯(IS-5-MN)。这2种代谢物在人体和动物体内都具有药理活性。作者用GLC法研究了静脉注射、舌下和口服途径给予ISDN后,健康人体内药物及其代谢物的动力学,以及这2种代谢物的生成速率。受试者为5名健康男性,年龄22～34岁,体重55～80kg。给药方法:静脉注射内含ISDN5mg的生理盐水溶液5ml,用5分     

5-单硝酸异山梨醇酯缓释胶囊治疗老年稳定型心绞痛临床观察

目的 :了解 5 单硝酸异山梨醇酯缓释胶囊对老年稳定型心绞痛的疗效。方法 :5 6例老年稳定性心绞痛患者 ,采用自身对照法 ,共观察 4周。前 2周为对照期 ,除维持 β受体阻滞剂及钙通道拮抗剂外 ,停用一切长效硝酸酯类药物。后 2周为治疗期 ,加用 5 单硝酸异山梨醇酯缓释胶囊 40mg ,qd。结果 :5 单硝酸异山梨醇酯缓释胶囊缓解心绞痛的有效率为 82 .1% ;用Holter监测 ,其减少心肌缺血发作的有效率为 88%。结论 :5 单硝酸异山梨醇酯缓释胶囊治疗老年心绞痛 ,具有持续作用长 ,副作用小 ,简便有效的优点     

5-单硝异山梨醇酯注射液对心力衰竭疗效及血流动力学的影响

目的：比较静脉滴注5－单硝异山梨醇酯（5－ISMN）与二硝酸异山梨醇酯（ISDN）注射液对充血性心力衰竭患者的疗效及血液动力学的影响。方法：采用随机,单盲的方法,将63例患者分成两组,分别给予5－单硝异山梨醇酯和二硝酸异山梨醇酯注射液20mg,测定两组病人用药前、后血压、心率、心功能及血液动力学指标。结果：5－单硝异山梨醇酯和二硝酸异山梨醇酯注射液显效率分别为43.75%和48.38%,总有效率分别为93.75%和96.76%,治疗后两组疗效显著,两组间无显著性差异。两药均有降低血压、心率,增加心排血量,改善心功能的作用。5－单硝异山梨醇酯治疗后,肺毛细血管楔嵌压、肺动脉平均压、右房压等指标下降。结论：5－单硝异山梨醇酯注射液与二硝酸异山梨醇酯注射液相同,对充血性心力衰竭有显著疗效。     

5-单硝酸异山梨醇酯联合普萘洛尔治疗肝硬化门静脉高压

目的观察5-单硝酸异山梨醇酯联合普萘洛尔对肝硬化门静脉血流动力学的影响。方法22例肝硬化患者口服5-单硝酸异山梨醇酯20mg,2次/d,普萘洛尔10～20mg,3次/d,共8周。于治疗前及治疗后4周、8周分别检测门静脉血流动力学参数。结果联合治疗后4周、8周均可以显著降低肝硬化患者门静脉内径、血流速度及血流量(P<0.01)。于治疗8周后,脾静脉内径也较治疗前缩小(P<0.05)。结论5-单硝酸异山梨醇酯联合普萘洛尔可以显著降低门静脉血流量。     

5—单硝酸异山梨醇酯缓释胶囊治疗老年稳定型心绞痛临床观察

目的：了解5-单硝酸异山梨醇酯缓释胶囊对老年稳定型心绞痛的疗效。方法：56例老年稳定性心绞痛患者,采用自身对照法,共观察4周,前2周为对照期,除维持β受体阻滞剂及钙通道拮抗剂外,停用一切长效硝酸酯类药物,后2周为治疗期,加用5-单硝酸异山梨醇酯缓释胶囊40mg/qd。结果：5-单硝酸异山梨醇酯缓释胶囊缓解心绞痛的有效率为82.1%;用Holter监测,其减少心肌缺血发作的有效率为88%。结论：5-单硝酸异山梨醇酯缓释胶囊治疗老年心绞痛,具有持续作用长,副作用小,简便有效的优点。     

Comparison of the initial hemodynamic effects of immediate-release versus sustained-release isosorbide-5-mononitrate following single oral doses

In this double-blind, randomized, placebo-controlled cross-over study, the authors investigated the initial time course of effects of isosorbide-5-mononitrate (IS-5-MN) on hemodynamic parameters in 15 healthy male volunteers after administering a single oral dose of either an immediate-release formulation (IS-5-MN 20 mg) or of a sustained-release formulation (IS-5-MN 50 mg). The latter formulation released 15 mg IS-5-MN immediately, while 35 mg of the dose was sustained release. The onset of effect on the a/b-ratio of the finger pulse curve (20 minutes after administration) and on heart rate following orthostatic challenge (30 minutes) was not different following ingestion of either the immediate-release or the sustained-release formulation. Only the systolic blood pressure following orthostatic challenge was affected earlier after ingestion of the immediate-release form of IS-5-MN (10 vs. 30 minutes). There was no statistically significant difference in the maximum effect on the measured hemodynamic parameters between the two formulations. There was no significant difference with respect to the effect per dose between both of the active treatments (i.e., IS-5-MN 20 mg immediate release and IS-5-MN 50 mg sustained release) within 6 hours after administration. The hemodynamic findings were consistent with the observed rates of the increase of plasma concentrations of IS-5-MN following both formulations. Thus, the administration of the sustained-release formulation of IS-5-MN 50 mg caused similar maximum effects when compared with an immediate-release formulation (20 mg). While the onset of effect of IS-5-MN on the a/b-ratio of the finger pulse curve and on heart rate following orthostasis was similar after administration of either the immediate- or the sustained-release formulation, the onset of effect of the sustained-release formulation on systolic blood pressure orthostasis was determined slightly later. However, the latter difference seems to be of minor clinical relevance.     

线粒体乙醛脱氢酶2基因多态性对5-单硝酸异山梨酯缓释片对健康受试者药物代谢的影响

目的 研究不同线粒体乙醛脱氢酶(ALDH2)基因型对5-单硝酸异山梨酯(IS-5-MN,抗心绞痛药)缓释片药物代谢的影响.方法 用PCR-RFLP测定ALDH2基因型后,分为2组,人组22名健康男性受试者.单次口服IS-5-MN 60 mg,血药浓度测定用HPLC-MS法;同时用脉搏波分析仪测量受试者脉搏波参数值;详细记录受试者的不良反应.结果 基因型为ALDH2*1/1和ALDH2*1/2的2组受试者在血药浓度、脉搏波参数、不良反应方面无明显差异;但同组内受试者的脉搏波参数值在服药前后有显著统计学差异(P＜0.05).结论 ALDH2基因多态性可能不影响IS-5-MN在健康受试者体内的代谢及药物作用.     

Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects

Summary In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values.The pharmacokinetic parameters (C_max, t_max, AUC, t_1/2) did not differ after morning and after evening dosing, t_max being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of IS-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN.The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.     

健康人乙醛脱氢酶2基因型对5-单硝酸异山梨醇酯缓释片药代动力学影响的研究

目的：探讨乙醛脱氢酶2基因（ALDH2）Glu504Lys（G504A）多态性对中国健康受试者口服5-单硝酸异山梨醇酯缓释片（IS-5-MN）药代动力学的影响。方法：在45例人群中筛选受试者,受试者单次口服IS-5-MN60mg,采集服药后36h内不同时间点的血样,HPLC-MS测定IS-5-MN的药物浓度。利用PCR-RFLP方法对ALDH2进行基因分型,分析不同基因型对IS-5-MN药代动力学的影响。结果：在45例人群中筛选出22名受试者,其中野生型纯合子13例,杂合子9例。两组基因型的IS-5-MN血药浓度和tmax差异没有统计学意义;尽管G/G基因型与G/A基因型相比,Cmax和AUC0-t分别升高了12.4%和15.3%,但差异均无统计学意义。结论：初步观察未发现ALDH2基因多态性与IS-5-MN的药代动力学有关。     

Evaluation of bioavailability and pharmacokinetics of two isosorbide-5-mononitrate preparations in healthy volunteers.

The objective of this study was to determine both the pharmacokinetic parameters and the bioavailability of two commercial 20-mg isosorbide-5-mononitrate (IS-5-MN) preparations (test and reference preparation) after single oral administration. For this purpose, the test and the reference preparation were examined in 24 healthy male volunteers according to a randomized 2-way cross-over design, blood samples were withdrawn up to 24 hours postadministration, and plasma concentrations of IS-5-MN were quantified by a gas chromatography (GC) method. Both preparations led to peak plasma levels of approximately 360 ng/mL IS-5-MN in the mean 0.76 hour (test) and 0.94 hour (reference preparation) after application; the plasma half-lives were about 5.2 hours, and for the areas under the curve (AUC(0-infinity)), mean values of 2741 (test preparation) and 2742 hour.ng/mL (reference preparation) were found. The statistical comparison (analysis of variance, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both IS-5-MN preparations. The undesired side effects/concomitant symptoms observed are known to occur after IS-5-MN administration.     

Pharmacokinetics of low-dose isosorbide dinitrate and metabolites after buccal or oral administration]

The kinetics of isosorbide dinitrate (ISDN; CAS 87-33-2) and its metabolites isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN) were examined after buccal and oral administration of 5 mg ISDN. Twelve healthy volunteers were included in a randomized cross-over study. The mean dose-corrected AUCs for total nitrate in serum after the two different preparations were in the same range. The relative bioavailability of ISDN applied buccally, however, was more than twice that after oral application. The metabolism of ISDN differed depending on the route of administration, where the AUC-ratios ISDN: IS-2-MN: IS-5-MN were 1:2.7:19.4 after buccal and 1:5.7:53.4 after oral application respectively. The absorption rate constants Ka for ISDN and the MRT after buccal and oral application did not differ significantly. The same holds for the mean residence time.     

Concentrations of isosorbide dinitrate,isosorbide-2-mononitrate and isosorbide-5-mononitrate in human vascular and muscle tissue under steady-state conditions

Summary The concentrations of isosorbide dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN) were determined in plasma (PL), saphenous vein wall (SV) and pectoral muscle (PM) from 8 patients undergoing coronary bypass surgery.The patients were pretreated for 2 days with ISDN 240 mg per day (standard release formulation) in 4 doses of 40 mg and one dose of 80 mg. The plasma and tissue samples were obtained during the operation, 10–12 h after the last dose.Isosorbide-2-mononitrate and isosorbide-5-mononitrate were present in plasma and tissues in the same concentration ranges with molar concentration ratios of 0.88 (IS-2-MN: PM/PL), 0.85 (IS-5-MN: PM/PL), 0.99 (IS-2-MN: SV/PL) and 1.06 (IS-5-MN: SV/PL). Mean ISDN concentrations in tissue were considerably higher than in plasma; the molar concentration ratios were 4.9 (SM/PL) and 7.21 (SV/PL).The accumulation of ISDN in vessel walls may contribute to its greater vascular action compared to the mononitrates, but it may also facilitate the development of tolerance during long-term treatment.     

Bioavailability and bioequivalence of organic nitrates. Isosorbide dinitrate--a study of sustained-release preparations

Assessment of Bioavailability of Organic Nitrates/Comparative bioavailability study of sustained-release isosorbide dinitrate preparations. Relative bioavailabilities of isosorbide dinitrate (ISDN, CAS 87-33-2) and the metabolite isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7) were studied after application of Maycor retard 40 (sustained-release capsules, multiple unit formulation, test preparation) in comparison to sustained-release tablets (single unit formulation, reference preparation) with 16 healthy male volunteers in a two-way crossover design. Test and reference formulations were previously characterised in vitro by dissolution tests. ISDN, IS-5-MN (IS-2-MN) plasma concentrations were determined using a selective and sensitive GLC-method with ECD-detection. As pharmacokinetic parameters AUC, Cmax and half value duration (HVD) were evaluated. Bioequivalence was assessed by calculating 90%-confidence intervals (ANOVA, ANOVAlog, Mann-Whitney-test) for ISDN and IS-5-MN. Bioequivalence was accepted if due to the inclusion rule one of the calculated intervals fulfill the requirements of 80 and 120% (AUC) or 70 and 130% (Cmax, HVD), respectively. Relative bioavailability of the test formulation was calculated as 94% (ISDN) and 96% (IS-5-MN). Maximum plasma concentrations of ISDN (IS-5-MN) were determined for the test preparation as 14.3 +/- 3.1 ng/ml (265 +/- 45 45 ng/ml) and as 22.8 +/- 12.6 ng/ml (287 +/- 59 ng/ml) for the reference product. HVD-values were for the test preparation 4.5 +/- 1.3 h (ISDN) and 8.5 +/- 1.3 h (IS-5-MN) and for the reference formulation 3.1 +/- 1.2 h (ISDN) and 8.1 +/- 1.4 (IS-5-MN).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of the bioavailability and pharmacokinetics of isosorbide dinitrate formulations in retard form and in standard preparations by determination of isosorbide-5-mononitrate

The aim of the study was to determine the relative bioavailability and the pharmacokinetic parameters following administration of a slow-release formulation of isosorbide dinitrate (ISDN, Isdin) capsules (20, 40 and 60 mg). A gas chromatographic method was used to determine the plasma concentrations of ISDN and isosorbide-5-mononitrate (IS-5-MN). All of the required pharmacokinetic parameters were ascertained. The study was performed on 12 healthy volunteers in a steady-state crossover design. A comparison of the areas under the plasma concentration/time curves of the test preparations and the commercial preparations showed higher values for the test preparations in all of the investigations. However, these values were only statistically significant for the 40 and 60 mg formulations ISDN and the 60 mg formulation IS-5-MN.     

Cutaneous metabolism of isosorbide dinitrate after transdermal administration in isolated perfused porcine skin

The purpose of this study was to determine whether isosorbide dinitrate (ISDN) was metabolized by the skin during transdermal delivery. In order to assess this, the isolated perfused porcine skin flap (IPPSF) was utilized since this in vitro model possesses a viable epidermis and intact vasculature, two attributes ideal for studying the biotransformation of a vasoactive drug. ISDN transdermal systems (20 cm²) were applied onto IPPSFs and the venous efflux sampled repeatedly over 16 h. ISDN, isosorbide-2-mononitrate (IS-2-MN), and isosorbide-5-mononitrate (IS-5-MN) fluxes were determined using gas chromatography. Approximately 14% of parent ISDN was metabolized to IS-2-MN and 10% to IS-5-MN. These observations are important as they indicate that a fraction of ISDN is biotransformed during transdermal delivery.