Isosorbide dinitrate inhibits platelet adhesion and aggregation in nonthrombolyzed patients with acute myocardial infarction

BACKGROUND: Apart from their vasodilatatory properties, nitrates have been shown to inhibit platelet aggregation. The effects of nitrates on platelet adhesion have not been studied. Nonselected patients with acute myocardial infarction (AMI) have been suggested to gain no benefit from administration of nitrates. However, the importance of nitrates may be greater in a subgroup of nonthrombolyzed patients with AMI. HYPOTHESIS: Isosorbide dinitrate (ISDN) decreases platelet adhesion and aggregation in nonthrombolyzed patients with AMI. METHODS: Consecutive 48 men with AMI, not eligible for thrombolytic therapy because of late presentation (> 12 h), were prospectively randomized 2:1 to double-blind ISDN (mean dose 2.4 +/- 0.9 mg/h) (n = 33) or placebo (0.9% sodium chloride) (n = 15) infusion. All patients received aspirin. Blood samples were taken at baseline (no study medication) and 3 h into ISDN or placebo infusion. Platelet adhesion to collagen was measured in the ethylene diamine tetraacetic acid (EDTA)-platelet rich plasma by recording changes in light transmission with an optical aggregometer. Platelet aggregation was measured using the Born's method. RESULTS: Isosorbide dinitrate significantly decreased both platelet adhesion and aggregation. No effect was seen in the placebo group. CONCLUSIONS: In patients with AMI who do not receive thrombolytic therapy, ISDN effectively inhibits platelet adhesion and aggregation. These effects of nitrates may be of therapeutic and prognostic significance in this group of patients.     

Plasma concentrations and coronary vasodilation after sublingual and intracoronary administration of isosorbide dinitrate

To investigate the relationship between plasma levels and coronary vasodilation after administration of isosorbide dinitrate (ISDN), the plasma concentration and diarneters of six segments of the left coronary artery were measured before and after sublingual (SL) ISDN (5 mg) and left intracoronary (IC) administration of ISDN (3 mg) in 12 patients. After SL-ISDN, the systolic aortic pressure decreased with no significant concomitant changes in heart rate or diastolic aortic pressure. After IC-ISDN, all hemodynamic parameters showed significant changes, and these were greater after IC-ISDN than those after SL-ISDN. The individual mean vasodilation of six segments induced by SL- and IC-ISDN, were 23± 9 and 35± 11% (p<0.01), respectively. Before SL-ISDN, ISDN was not detected in plasma. After SL- and IC-ISDN, however, the plasma values of the ISDN were 36.1± 53.3 and 101.5± 90.0 ng/ml (p<0.01), respectively. Thus, both coronary vasodilative responses and plasma ISDN levels after IC-ISDN were significantly greater than those after SL-ISDN. However, neither the individual mean coronary vasodilation nor the hemodynamic changes correlated significantly with plasma ISDN levels. Consequently, with administration of the same dose, the coronary vasodilative response to ISDN did not correlate with plasma levels. Furthermore, IC-ISDN dilates coronary arteries more effectively than SL-ISDN.     

硝酸异山梨酯对大鼠缺血心肌血管新生的影响

目的观察硝酸异山梨酯对急性心肌梗死(AMI)大鼠缺血心肌组织形态、梗死面积及毛细血管新生的影响。方法Wistar大鼠90只建立AMI模型后,随机分为5组,分别为正常组,假手术组,模型组,硝酸异山梨酯低剂量组(IDL组)和硝酸异山梨酯高剂量组(IDH组),每组18只。大鼠饲养7、14天后各随机处死9只,截取心肌组织,进行光镜、电镜观察,利用NBT染色法测定心肌梗死面积,应用免疫组织化学法测定Ⅷ因子,进而计算缺血心肌微血管密度(MVD),通过RT-PCR技术检测血管内皮生长因子(VEGF)及碱性成纤维细胞生长因子(bFGF)基因表达情况。结果光镜下观察,缺血区可见炎细胞浸润、心肌肿胀、梗死区纤维化。与模型组比较,IDL组和IDH组7、14天心肌梗死面积明显缩小,MVD明显增加(P<0.05);正常组、假手术组VEGF mRNA、bFGF mRNA表达有所减少,而IDH组则有所增加。结论硝酸异山梨酯可明显缩小AMI大鼠梗死面积,促进缺血心肌的毛细血管新生,对心肌缺血损伤具有保护作用。     

Acute and subacute effects of nicorandil and isosorbide dinitrate on vessel wall properties of large arteries and hemodynamics in healthy volunteers

Summary Nicorandil (N) and isosorbide dinitrate (ISDN) are vasodilator drugs used in patients with angina. In 24 healthy male volunteers (18–32 years), the acute effect of a single oral dose (20 mg) of N and ISDN on arterial diameter (D), distensibility, and compliance of the elastic common carotid artery (CCA) and the muscular femoral (FA) and brachial (BA) arteries were investigated. The effects on systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), and venous hemodynamics were also assessed. In addition, the subacute effects after 8 days of treatment with N (2×20 mg/day) and ISDN (3×20 mg/day) on these parameters were evaluated. After a 20 mg single oral dose, blood pressure decreased significantly more with ISDN (SBP: 6%; DBP: 14%) than with N (SBP: 2%; DBP: 6%), but after 8 days this decrease in blood pressure was not statistically different between ISDN and N. The diameter of CCA increased more with ISDN (11%) than N (5%) acutely as well as subacutely (ISDN: 12%; N: 9%). Heart rate increased only with ISDN (7% acutely, 3% subacutely). No differences between ISDN and nicorandil were found for acute and subacute effects on SVRI, venous hemodynamics, diameter of muscular arteries (FA, BA), and the distensibility and compliance of elastic (CCA) and muscular (FA, BA) arteries. Day 1 to day 8 changes in heart rate and cardiac index were small but differed between ISDN and nicorandil. These differences were due to a smaller increase in HR and CI at day 8 than at day 1 with ISDN. Data on blood pressure and heart rate are in accordance with drug tolerance seen with ISDN but not with nicorandil. However, ISDN drug tolerance was not seen for the diameter of large arteries. In conclusion, with dosages used in angina, compared to nicorandil—a drug with both a potassium channel opening property and a nitratelike action—the pure nitrate ISDN showed a more pronounced decrease in systolic and diastolic blood pressure, a slight increase in heart rate, and more vasodilation of CCA. ISDN drug tolerance was shown for blood pressure and heart rate. In contrast to the well-known venous tolerance during ISDN, there was no ISDN drug tolerance for the effects on diameter of large arteries. No drug tolerance was seen with nicorandil.     

Effects of Amlodipine and Isosorbide Dinitrate on Exercise-Induced and Ambulatory Ischemia in Patients with Chronic Stable Angina Pectoris

This study was designed to compare once-daily administration of 5–10 mg amlodipine with two daily doses of 40 mg sustained-release isosorbide dinitrate in 59 patients with stable angina using a randomized, double-blind, crossover study design. Anginal episodes, nitroglycerin consumption, and possible adverse events were recorded in a diary. A maximal symptom-limited bicycle exercise test and 48-hour ambulatory ECG monitoring were performed at baseline and at the end of each 5-week period of therapy. Exercise time, time to angina, time to ST depression, and maximal ST depression were measured during exercise. During ambulatory monitoring, the number of ischemic episodes and the duration per hour of ST depression were assessed. Amlodipine significantly reduced anginal episodes (P < 0.001) when compared with isosorbide dinitrate. Furthermore, amlodipine prolonged time to ST depression (P < 0.001) and time to angina (P < 0.05) when compared with isosorbide dinitrate. The number and duration of ischemic episodes during ambulatory monitoring were significantly reduced with amlodipine when compared with baseline values (P < 0.05), whereas no differences were found between isosorbide dinitrate and baseline. Adverse events were reported more frequently with isosorbide dinitrate than with amlodipine (P < 0.02). Amlodipine appears to be more effective and tolerable than sustained-release isosorbide dinitrate as monotherapy for chronic stable angina. This revised version was published online in July 2006 with corrections to the Cover Date.     

硝酸异山梨酯气雾剂的药物动力学及相对生物利用度

采用毛细管气相色谱－电子捕获法测定１２名健康男性受试者单剂量舌下交叉喷服国产和进口硝酸异山梨酯气雾剂５ｍｇ后的血药浓度。结果两者的ｋ分别为０．８７２、０．７３６ｈ＾－１，Ｔｍａｘ为０．２４３、０．２０８ｈ，Ｃｍａｘ为４．５２１、４．６２８μｇ／Ｌ，国产气雾剂的相对生物利用度为９５．３５％。     

Continuous long-term dosing with oral slow-release isosorbide dinitrate does not reduce incidence of cardiac events in patients with healed myocardial infarction

BACKGROUND: In the short term, isosorbide dinitrate (ISDN) is considered to be therapeutically effective. The long-term effects of treatment with slow-release ISDN are less clear. HYPOTHESIS: The study was undertaken to investigate the effects of continuous, long-term dosing with oral slow-release ISDN on the incidence of cardiac events in patients with healed myocardial infarction (MI). The study was carried out in accordance with the intention-to-treat principle. METHODS: In all, 1.102 in- and outpatients, of either gender, with healed MI were randomly divided into groups treated with ISDN (n = 470) and not treated with ISDN (n = 632). Patients in the ISDN group received a continuous regimen of 20 mg of oral, long-acting ISDN three times a day, after meals. The mean observation period was 15.0 +/- 18.5 months. The primary endpoints were nonfatal and fatal recurrent MI, death from congestive heart failure, and sudden death. RESULTS: There were no significant differences in the baseline characteristics of the patients in the ISDN and no-treatment groups; nevertheless, significantly more patients in the ISDN group experienced cardiac events. In the ISDN group, 35 patients (7.4%) experienced cardiac events during the observation period, versus only 28 patients (4.4%) in the no-treatment group (p < 0.05; odds ratio 1.74; 95% confidence interval 1.04-2.90). CONCLUSION: Continuous long-term dosing with oral, slow-release ISDN does not reduce and probably increases the incidence of cardiac events among patients with healed MI.     

Comparative vasodilator effects of nitroglycerin,pentaerythritol trinitrate and biometabolites,and other organic nitrates

Previous studies in man have shown pentaerythritol (PE) trinitrate, given either sublingually or orally, produces a prolonged hypotensive effect. The coronary vasodilator and systemic vasoddepressor activities of PE trinitrate and its metabolites, PE dinitrate, PE mononitrate and PE, were evaluated in dogs to determine whether the metabolites were active and contributory. Coronary vasodilator activity was estimated with a flow transducer placed on the left anterior descending artery, and reduction of arterial pressure was determined directly via the femoral artery. Quantitative comparisons were made from dose—response curves established for nitroglycerin (NG), PE nitrates, and other common organic nitrates after intrajugular administration. Increase of coronary blood flow and reduction of arterial pressure were proportionally related, and the proportionality was the same for all drugs. Relative to NG, the potency of PE trinitrate was about 20%, erythrityl tetranitrate 12%, and isosorbide dinitrate 3.5%. The ratios of vasodilator activity of PE trinitrate and its metabolites were: PE trinitrate 100; PE dinitrate 1.5; PE mononitrate 0.5; and PE 0. Tachyphylaxis was observed after close-order injections of NG or PE trinitrate. In addition, there was cross tolerance between NG and PE trinitrate and also between PE trinitrate and its less active metabolites.     

Composition analysis of two batches of polysorbate 60 using MS and NMR techniques

Batch variation in Tween 60 has shown to influence the rheological properties of semisolid emulsions. MS (LC–MS, GC–MS, MSⁿ) and NMR (¹³C, ¹H, ¹H COSY and HMBC) techniques were used to analyze and compare the composition of two batches of Tween 60 with particular emphasis on the number of POE groups and their distribution within the molecule. Acid and saponification values were also determined. The batches contained different proportions of components (sorbitan polyethoxylates, sorbitan monoester–diester-polyethoxylates and isosorbide monoester–diester-polyethoxylates). The number of POE groups were averaged over the four sites in sorbitan and the two sites in isosorbide molecules. The batches differed from each other in terms of (i) the POE sorbitan stearate/POE sorbitan palmitate ratios (batch 1, 3:2 and batch 2, 4:5), (ii) the ratio of sorbitans to isosorbides (batch 1, 2:3; batch 2, 7:13); and (iii) the acid values (batch 1, 3.1; batch 2, 0). It is concluded that liquid chromatography combined with electrospray mass spectrometry and ion trap separation is a useful tool for establishing the compositional profile of different batches of Tweens. ¹H NMR could provide a simple and rapid pharmacopoeial test for the ratio of sorbitan to isosorbide in Tweens.