单硝酸异山梨酯孪药合成及其性能研究

 目的设计并合成单硝酸异山梨酯与阿司匹林组成的孪药,评价该类前药的药理作用和生物活性。方法对单硝酸异山梨酯孪药进行了IR、MS、NMR结构确证,测定了脂水分配系数、血浆酶催化水解速率、体外药理活性、胃肠道刺激性。结果单硝酸异山梨酯孪药(Prodrug 1,Prodrug 2)的logP值分别为0.89、0.45,在血浆中水解t_1/2(2～4min);对二磷酸腺苷(ADP)诱导血小板聚集抑制率为50.9%～52.4%。结论单硝酸异山梨酯组合前药在血浆迅速水解为原药及相关产物,与阿司匹林比较抗血小板活性相近,胃肠道刺激性明显减小。     

硝酸酯类对老年单纯收缩期高血压的影响

目的比较依那普利和氢氯噻嗪加用与不加用单硝酸异山梨酯（ISMN）两种方案对老年单纯收缩期高血压（ISH）的降压疗效及安全性。方法110O例轻、中度老年ISH患者,随机分为A组60例,给予ISMN缓释片（40mg／d）、依那普利（10mg／d）、氢氯噻嗪（12．5mg／d）,晨顿服;B组50例,给予依那普利（10mg,每日2次）,氢氯噻嗪（25mg／d）,均治疗8周。治疗前后测动态血压、诊室血压、心率及生化指标。结果A组总有效率在诊室血压为91．67％,动态血压为86．12％;B组分别为80．00％和74．29％。24h昼夜平均收缩压下降A组大于B组;收缩压谷/峰比及平滑指数A组高于B组（谷／峰比：0．75,0．59;平滑指数：0．86,0．65）。两组比较差异有统计学意义（P〈0．05）。结论硝酸酯等三药联用。可以24h平稳降低轻、中度老年ISH患者的血压,好于常规两药联用,安全性良好。     

硝酸酯类药物口服与静脉联合应用疗效及合理性评价与分析

目的：对某医院硝酸酯类药物口服与静脉联合应用疗效及合理性评价与分析,为临床应用提供参考。方法采用样本分析方法,收集2015年3月至2016年3月某医院心血管内科使用硝酸酯类药物的300份病历,统计分析使用剂型及联合用药对疗效和不良反应（ ADR）的影响。结果联合应用与单独应用某一剂型相比总有效率并无显著性差异（P＞0．05）,联合应用口服加静滴的患者出现ADR时间早、ADR发生率高,以头痛症状为主。结论口服联合静脉给予硝酸酯类药物治疗冠心病心绞痛疾病时,较单独给予一种剂型时疗效并无明显增强,但不良反应出现加快,耐药性产生加快。     

（Ⅱ）国产单硝酸异山梨醇酯对小鼠耐缺氧作用研究

本文对国产单硝酸异山梨醇酯(ISMN)采用不同方法进行耐缺氧作用观察,(1)窒息法;(2)测定氧消耗量法;(3)夹闭气管法。并与阳性药物心得安和前体药物消心痛(ISDN)进行对比分析。结果显示ISMN对前两种方法无显著的耐缺氧作用,而对第三种方法有显著的阳性结果,且实验结果与消心痛基本一致,心得安则对第一种方法取得极其显著的阳性反应,从而证实了ISMN对小鼠具有一定的心血管性昏耐缺氧作用。提示此三种方法对不同原理的药物可取得不同的结果,同时也反证了耐缺氧研究应采用多种方法之必要性。     

(Ⅲ)国产单硝酸异山梨醇酯对异丙肾上腺素引起大鼠心肌损伤的保护作用

本文用腹腔注射异丙基肾上腺素(Iso)造成大鼠心肌缺血性损伤模型,研究了国产单硝酸异山梨醇酯(ISMN)对大鼠心肌损伤的影响。ISMN能降低Iso引起的S-T段抬高,减少心肌肌酸磷酸激酶(CPK)的丢失;其口服给药的作用强度与二硝酸异山梨醇酯(ISDN)相似。实验结果提示国产ISMN对Iso引缺的心肌缺血性损伤有保护作用,其机理可能包括对心肌本身的直接作用。     

Study on dissolution and absorption of four dosage forms of isosorbide mononitrate: Level A in vitro–in vivo correlation

The objective of the present study was to develop a novel in vitro system to simulate the process of dissolution and permeation of oral solid dosage forms in vivo, and to establish a correlation between in vitro permeation and in vivo absorption that could predict the bioavailability (BA) and bioequivalence (BE) of congeneric products. The in vitro dissolution and absorption kinetics of four dosage forms of isosorbide mononitrate (ISMN) were evaluated by the USP basket/paddle system and drug dissolution/absorption simulating system (DDASS). The corresponding pharmacokinetic study was performed in beagle dogs. A comparative study was carried out between the classical and the novel method to estimate the effectiveness of the modified DDASS in simulating the course of dissolution and absorption in vivo. Indeed, the correlation coefficients of in vitro dissolution and in vivo absorption obtained from DDASS and dogs were higher. Moreover, a higher level A in vitro–in vivo correlation (IVIVC) between DDASS permeation and dog absorption was established, with correlation coefficients of 0.9968, 0.9872, 0.9921, and 0.9728. The DDASS method was more accurate at modeling the process of dissolution and absorption in vivo for both immediate-release (IR) and sustained-release (SR) dosage forms of ISMN.     

Evaluation of Endoscopic Variceal Ligation (EVL) Versus Propanolol Plus Isosorbide Mononitrate/Nadolol (ISMN) in the Prevention of Variceal Rebleeding: Comparison of Cirrhotic and Noncirrhotic Patients

Both EVL and drug therapy are effective in the prevention of variceal rebleeding. Comparisons between the two modalities are few, and only in cirrhotics. This prospective randomized controlled trial compared EVL with drug therapy (propranolol + ISMN) in the prevention of rebleeds from esophageal varices in cirrhotic and noncirrhotic portal hypertension (NCPH) patients. One hundred thirty-seven variceal bleeders were randomized to EVL (Group I; n = 71) or drug therapy (Group II; n = 66). In Group I, EVL was done every 2 weeks till obliteration of varices. In Group II, propranolol (dose sufficient to reduce heart rate to 55 bpm/maximum tolerated dose) and ISMN (incremental dose up to 20 mg BD) were administered. Group I and II patients had comparable baseline characteristics, follow-up (12.4 vs. 11.1 months), cirrhotics and noncirrhotics [50(70.4%) and 21(29.6%) vs. 51(77.3%) and 15(22.7%)] and frequency of Child’s A (35 vs. 27), B (26 vs. 28), and C (9 vs. 11). The mean daily dose was 109 ± 46 mg propranolol and 34 ± 11 mg ISMN and was comparable in cirrhotic and NCPH patients. Upper GI bleeds occurred in 10 patients in Group I (5 from esophageal varices) and in 18 patients in Group II (15 from esophageal varices) (P = 0.06). The actuarial probability of rebleeding from esophageal varices at 24 months was 22% in Group I and 37% in Group II (P = 0.02). The probability of bleed was significantly higher in Child’s C compared to Child’s A/B cirrhotics (P = 0.02). On subgroup analysis, in NCPH patients, the actuarial probability of bleed at 24 months was significantly lower in Group I compared to Group II (25% vs 37%; P = 0.01). In cirrhotics, there was no difference in the probability of rebleeding between patients in Group I and those in Group II (P = 0.74). In Group II, 25.7% patients had adverse effects of drug therapy and 9% patients had to stop propranolol due to serious adverse effects, none required stopping ISMN. There were 10 deaths, 6 in Group I (bleed related, 1) and 4 in Group II (bleed related, 1); the actuarial probability of survival was comparable (P = 0.39). EVL and combination therapy are equally effective in the prevention of variceal rebleeding in cirrhotic patients. EVL is more effective than drug therapy in the prevention of rebleeds in patients with NCPH and, hence, recommended. However, in view of the small number of NCPH patients, further studies are needed before this can be stated conclusively.     

5-单硝酸异山梨酯缓释胶囊的人体生物等效性

采用GC法测定 5 单硝酸异山梨酯血浆药物浓度 ,研究 5 单硝酸异山梨酯缓释胶囊相对生物利用度和生物等效性。 18名健康志愿者随机交叉单剂量口服试验药 (T)与对照药 (R) 4 0mg ,测得Cmax分别为 (348 3± 146 8)ng/mL和 (347 9± 2 0 2 4)ng/mL ;Tmax 分别为 (4 7± 1 8)h和(4 6± 1 7)h ;AUC( 0 -n) 分别为 (3 933 2± 142 5 0 )ng h/mL和 (3 6 93 0± 12 39 5 )ng h/mL ;相对生物利用度为 (10 6 6± 16 9) %。 18名志愿者随机交叉多剂量口服T与R ,测得达稳态的Cmax分别为 (2 30 9± 72 4)ng/mL和 (190 9± 6 6 9)ng/mL ;Cmin分别为 (4 2 6± 2 3 5 )ng/mL和 (4 7 4±2 2 1)ng/mL ;AUCSS分别为 (2 939 4± 92 2 1)ng h /mL和 (2 6 6 7 4± 832 9)ng·h /mL ;DF分别为1 6± 0 4和 1 3± 0 3 ;相对生物利用度为 (111 0 2± 2 1 0 5 ) %。经生物等效性分析 ,两制剂在单剂量与多剂量条件下生物等效     

单硝酸异山梨酯对小鼠损伤血管修复的影响

目的研究单硝酸异山梨酯对小鼠损伤血管修复的影响。方法采用电刺激小鼠颈总动脉制备血管损伤模型,再应用伊文思蓝染色研究损伤血管内皮修复过程。通过测定血管收缩、内皮依赖性舒张和非内皮依赖性舒张来评估NO对损伤血管功能恢复的影响。结果经单硝酸异山梨酯预处理一周（7 d）和一个月（30 d）的损伤血管,跟生理盐水对照组相比,在内皮修复过程中没有显著性差异,同时血管平滑肌细胞没有显著性改变。经过单硝酸异山梨酯预处理的小鼠损伤血管的功能也没有改善。结论血管平滑肌的修复并不是再生,平滑肌的修复主要靠已有平滑肌细胞的迁移,短期应用单硝酸异山梨酯可一定程度上抑制损伤后血管内膜增厚和血管重构。     

国产单硝酸异山梨醇酯药理研究——(Ⅰ)国产单硝酸异山梨醇酯对正常大鼠血流动力学的影响

国产ISMN对正常大鼠在早期均可使血压显著降低(P<0.01),但随即迅速恢复,在其他血流动力学指标方面,LVSP和LVEDP值均明显低于对照组(P<0.01),对±dp/dtmax与HR均无影响(P<0.05),但在25mg/kg剂量时,±dp/dtmax降低明显(P 0.01),实验结果表明,国产ISMN作为一种抗心绞痛新药,有进一步研究的价值。