【摘要】 第一部分5-单硝酸异山梨酯对健康受试者外周和中心动脉压的影响目的研究单剂和连续6天服用5-ISMN,对健康受试者外周和中心动脉血压的动态影响。方法采用受试者自身对照的方法。(1)基线组(对照组):受试者第一天在不服药的空白状态下,分别于6:30、7:30、8:00、9:00、10:00、11:00、12:00、13:00、15:00、19:00、23:00时测量每个受试者的心率、血压、脉搏波,作为基线对照。(2)单剂量组:受试者于试验第二天晨7:00,空腹单次口服5-ISMN(商品名:依姆多)60mg,用250mL温开水送服。在与前一天相同的时间点:即服药前0.5h、服药后0.5h、1h、2h、3h、4h、5h、6h、8h、12h、16h测量受试者的心率、血压、脉搏波和血药浓度。(3)多剂量组:第三天为药物洗脱期。从第四天起,受试者每天早上7:00空腹口服5-ISMN60mg,一天一次,连续6d。在第九天,与单次服药后相同的时间点,测量每个受试者的心率、血压、脉搏波和血药浓度。在实验期间禁烟酒和其他药物,并禁剧烈运动。本文研究的参数包括:心率、外周收缩压、外周舒张压、外周脉压和脉搏波参...更多数。其中脉搏波参数包括:中心动脉收缩压、中心动脉舒张压、中心脉压(CPP)和反射波增压指数(AI)。结果与基线组比较,服用单剂量和多剂量5-ISMN后,外周收缩压、外周舒张压和外周脉压、中心动脉舒张压和心率无显著差异(P＞0.05)。单次服用5-ISMN后,中心收缩压和中心脉压有显著下降(P＜0.05)。在服药后1h、2h、3h、降低的幅度最大,与基线同一时间点比较,下降的幅度分别为:(10.94±3.18mmHg、11.29±2.70mmHg、6.90±3.38mmHg)和(4.82±1.60mmHg,5.94±1.59mmHg、7.41±1.50mmHg)。而服用多剂量5-ISMN后,中心收缩压和中心脉压虽然在个别时间点稍微有些下降,但整体比较则无统计学差异(P＞0.05)。健康受试者服用5-单硝酸异山梨醇酯单次和多次后,AI均显著降低,差异有统计学意义(P＜0.05),此效应持续12小时。服用单剂量5-ISMN后0.5h,AI开始下降,在1小时下降幅度最大,下降(33.8±4.5)%;在服药后5小时内,随着血药浓度的急剧上升,AI并没有相应地降低,而是维持在稳定水平。多次服用5-ISMN药后,AI在1小时达下降最低点,下降(21.2±4.6)%。但与单剂量相比,多剂量组AI反而上升(P=0.046 RMANOVA)。其中在服药后1h、2 h时间点,AI差异有统计学意义(P＜0.05)。结论5-单硝酸异山梨醇酯能明显降低中心动脉脉压和中心动脉收缩压,并且能明显改善血管顺应性但易产生耐受性。第二部分探讨5-单硝酸异山梨酯对健康受试者血清sVCAM-1的影响目的检测健康受试者连续服用5-单硝酸异山梨醇酯后,血清可溶性血管细胞间黏附分子-1(sVCAM-1)的水平,旨在探讨它们之间的关系,及其在硝酸酯类药物耐受性发生、发展中的作用,并为耐药性的防治提供理论依据。方法18例健康男性志愿者,服用IS-5-MN,60mg,qd,连续7d,每天早上7:00空腹250mL温开水送服。在服药前一天、服药第二天、第六天以及第九天分别于早6:30抽取静脉血。采用双抗体夹心酶联免疫吸附试验(ELISA)法,对不同时间点受试者血中sVCAM-1水平进行检测。结果健康受试者在服用5-单硝酸异山梨醇酯前后,血清中sVCAN-1浓度分别为:服药前一天(310.80±95.32)ng/mL,第二天(342.16±158.83)ng/mL,第六天(334.52±85.08)ng/mL,第九天(306.46±68.28)ng/mL。不同时间点sVCAN-1浓度采用重复测量方差分析,结果显示未见统计学差异(P＞0.05)。结论健康受试者连续7天服用5-ISMN后,用ELISA方法检测不同时间点血清中sVCAM-1浓度,未见sVCAM-1浓度有明显的变化。第三部分ALDH2基因型对5-单硝酸异山梨酯药代动力学的影响目的探讨乙醛脱氢酶2基因(ALDH2) Glu504Lys多态性对中国健康受试者口服5-单硝酸山梨醇酯缓释片药代动力学的影响。方法在45例人群中筛选出22名受试者,受试者单次口服5-单硝酸异山梨醇酯缓释片(5-ISMN)60mg,在服药前和服药后0.25、0.5、1、2、3、4、5、6、8、12、16、24和36h取静脉血2mL。HPLC-MS测定5-ISMN的药物浓度;利用PCR-RFLP及直接测序方法对受试者ALDH2进行基因分型。分析不同基因型对IS-5-5MN药代动力学的影响。结果22名受试者中野生型纯合子(G/G)13例,杂合子(G/A)9例。两组基因型的5-ISMN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%,但差异均无统计学上意义。结论在22例健康受试者中,初步观察未发现ALDH2基因多态性与5-ISMN的药代动力学有关,需扩大样本进一步验证。 

【Abstract】 Part 1The effect of extended-release isosorbide-5omononitrate on brachial blood pressure and central aortic pressure on healthy volunteersObjectiveTo investigate the effects of isosorbide-5-mononitrate on brachial blood pressure, central arterial pressure and arterial elasticity of healthy volunteersMethodsThis is a self-controlled study.(1) Control group:Parameters of pulse wave analysis, heart rate and blood pressure were measured in the pre-dose day at 6:30,7:30,8:00, 9:00,10:00,11:00,12:00,13:00,15:00,19:00,23:00 as baseline.(2)Single dose group:In the second day,60mg 5-ISMN was administered orally with 250ml warm water at 7:00 on an empty stomach.Parameters of pulse wave analysis,heart rate and the blood concentration of 5-ISMN were measured at the same time at the first day.(3)Multiple dose group:the third day as the period of elution,from the forth day,60mg IS-5-MN was administered consecutively for six days at 7:00,parameters of pulse wave analysis,heart rate,the blood concentr...ation of 5-ISMN were measured in the ninth day at the same time. The parameters of PWA includes AI(Augmentation Index),CSP(central Systolic Pressure),CDP(central diastolic pressure),CPP(central pulse pressure).During the clinical trial period,all healthy subjects were not allowed to take other medicine,smoke and drink wine and forbidden to do heavy exercise.ResultsBoth single and multiple IS-5-MN administration markedly reduced AI and central artery pulse pressure.After six days of consecutive administer,these effects were significantly attenuated but did not disappear completely.Brachial blood pressure and heart rate had no significant change.ConclusionIS-5-MN improves the artery compliance and reduce central artery pulse pressure in healthy male volunteers,but is associated with development of vascular tolerance. Part 2The effect of consecutive administered extended-release isosorbide-5-mononitrate on sVCAM-1 level in healthy volunteersObjectTo investigate effectiveness of 7days consecutive administered isosorbide-5-mononitrate on sVCAM-1 level of serum in healthy volunteers.MethodsIsosorbide-5-Mononitrate(IS-5-MN) 60mg was administered to 18 healthy male volunteers once daily for consecutive 7 days.The serum sVCAM -1 levels of healthy volunteers were measured by Enzyme- linked Immunosorbent Assay(ELISA)at the pre-dose day,the second dose day and the sixth dose day and the ninth day.ResultsThe serum sVCAM -1 levels of healthy volunteers did not show significant statistical difference at various time(P＞0.05).ConclusionIn our research,the continuous 7days effectiveness of isosorbide-5-mononitrate could not influence on sVCAM-1 level in serum in healthy volunteers. Part3Relationship between polymorphisms of aldehyde dehydrogenase 2 gene and pharmacokinetic characteristics of isosorbide-5-mononitrate in Chinese healthy subjectsObjectTo investigate the relationship between the mutation in aldehyde dehydrogenase 2 gene(ALDH2) at positions Glu504Lys and pharmacokinetic(PK) characteristics of isosorbide-5-mononitrate(5-ISMN) in Chinese healthy volunteers.MethodsAmong 45 persons,twenty-two healthy male volunteers were selected and orally administered 60 mg 5-ISMN.HPLC-MS method was applied to analyze 5-ISMN plasma concentration.ALDH2 genotype was determined by PCR- RFLP. Pharmacokinetic analysis was performed and the effects of the genotypes on 5-ISMN pharmacokinetics was assessed.ResultsIn these 22 volunteers,13 homozygous GG and 9 heterozygous GA genotypes for ALDH2 at positions of Glu504Lys were detected by PCR- RFLP.5-ISMN plasma concentration,AUC0-t,Cmax and Tmax did not show significant statistical difference between the two groups genotypes(P＞0.05).ConclusionThe polymorphisms of ALDH2 gene at positions of Glu504Lys could not influence the pharmacokinetics of 5-ISMN in our research. 

【关键词】 5-单硝酸异山梨醇酯; 脉搏波分析; 反射波增强指数; 耐受性; 5-单硝酸异山梨醇酯; 可溶性血管细胞间黏附分子-1(sVCAM-1); 内皮损伤; 耐受性; 5-单硝酸异山梨醇酯缓释片; 乙醛脱氢酶2; 基因多态性; 药代动力学
【Key words】 Isosorbide-5-Mononitrate; Pulse Wave Analysis; Augment Index; Tolerance; Isosorbide-5-Mononitrate; Endothelium dysfunction; Toleration; Vascular Cell Adhesion Molecule-1 (VCAM-1); Isosorbide-5-Mononitrate ; Aldehyde Dehydrogenase 2; Genetic Polymorphism; Pharmacokinetics