Clinical pharmacokinetics of nitrates

Summary The pharmacokinetics of organic nitrates are discussed with emphasis on the possible clinical relevance. For glyceryl trinitrate, the measurement of plasma concentrations is very difficult. Its pharmacokinetics are unusual, with a very rapid disappearance from plasma, and large intraindividual and interindividual variations. After oral administration, there seems to be a very extensive first-pass hepatic extraction and the plasma concentrations are often below the detection limit; after sublingual administration, glyceryl trinitrate appears in plasma. With transdermal glyceryl trinitrate controlled-release systems, plasma concentrations of glyceryl trinitrate can be maintained over 24 hours, although with fluctuations and important intraindividual and interindividual variability. After administration of glyceryl trinitrate via different routes, glyceryl dinitrates and mononitrates are present in plasma. The pharmacokinetics of isosorbide dinitrate are somewhat easier to understand. The substance disappears less rapidly from the plasma than does glyceryl trinitrate. After oral administration, there is also a hepatic first-pass extraction; the plasma concentrations can be prolonged by administering slow-release products. Sublingual administration leads to higher plasma concentrations than oral administration. Isosorbide dinitrate is metabolized in the organism to isosorbide 5-mononitrate and isosorbide 2-mononitrate, which both have vasodilator activity: after administration of isosorbide dinitrate, the mononitrates, and mainly the 5-mononitrate, reach very high concentrations in plasma. Isosorbide 5-mononitrate has been studied in its own right as an antianginal agent: it is completely absorbed after oral administration; it has a half-life of around 4 hours, and oral standard and controlled-release formulations have been extensively studied. For several reasons, including attenuation of the effects with time and the appearance of active metabolites, the relationship between the plasma concentrations of nitrates and their therapeutic effects is very complex. Knowledge of the pharmacokinetics of these substances is only of limited interest.     

Massive ingestion of isosorbide-5-mononitrate and nitroglycerin: suicide attempt by an adolescent girl without previous heart disease

High plasma levels of isosorbide-5-mononitrate were found ina young girl who had ingested 1.6 g of the drug plus 20mg ofnitroglycerin. These concentrations produced no disturbanceof the patient's state of consciousness and no serious haemodynamiceffects appeared except for a tachycardia in relation to peripheralvasodilatation.     

Short and long-acting oral nitrates for stable angina pectoris

Summary Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing regimens of controlled-release formulations of isosorbide dinitrate (ISDN) and controlled-release NTG during long-term therapy have not been established. Use of immediate-release formulation of 15–120 mg of ISDN in a qid regimen lead to a marked reduction in the size and duration of antianginal effects compared to the initial dose. Asymmetric tid therapy with 30 mg of ISDN (7 a.m., 1 p.m, and 6 p.m.) is also associated with the development of partial tolerance and appears to provide antianginal prophylaxis for only a period of 6 hours each day. Asymmetric bid therapy with ISDN at 7 a.m. and noon may give sustained effect but is supported by only a single, small study that did not examine effectiveness after the noon dose in long-term use. Isosor-bide-5-mononitrate (IS-5-MN) has been the subject of more recent studies than other nitrates because of attempts to bring a number of products into the U.S. market. IS-5-MN in qid, tid, and standard bid (8 a.m. and 8 p.m.) dosing regimens produce tolerance. Asymmetric regimens of immediate-release IS-5-MN (10 and 20 mg) given bid (once in the morning and again 7 hours later) decrease the development of tolerance compared to symmetric regimens and produce an increased exercise duration after each dose of the day; the 20 mg bid dosing is more effective. Similarly, once-daily 120 and 240 mg controlled-release IS-5-MN does not produce tolerance and gives a sustained increase in daytime exercise duration. Both asymmetric bid immediate-release and once-daily controlled-release IS-5-MN preparations do not produce deterioration in exercise performance prior to the administration of the medication in the morning (i.e., no zero-hour effect). Further studies are needed to establish useful dosing regimens for ISDN, for controlled-release ISDN, and for controlled-release nitroglycerin. None of the dosing regimens of any oral, long-acting nitrate (including IS-5-MN) provide 24 hour antianginal and antiischemic effects. Although it is intuitively attractive to add an agent (beta-blocker or calcium channel blocker) that exerts 24 hour antianginal and anti-ischemic effects, which appear to depend on mechanisms different from those of nitrates, there are no studies that allow an evaluation of the usefulness of adding beta-blockers or calcium channel blockers to nitrate therapy (or vice versa).The opinions expressed here are those of the authors and should not be taken as those of FDA.     

Mechanisms of nitrate tolerance: A review

Summary With the increased use of long-acting nitroglycerin preparations, there has been greater recognition of the problem of nitrate tolerance. In recent years extensive research has broadened our understanding of the mechanisms of nitroglycerin action and the mechanisms of drug attenuation. This paper reviews the current state of knowledge regarding nitroglycerin tolerance, with an emphasis on the concepts of cellular and neurohumoral mechanisms of drug attenuation. The discussion includes potential approaches to prevent nitrate tolerance, including the introduction of a nitrate-free interval, or concomitant administration of sulfhydryl donors or neurohumoral blocking agents.     

The effects of oral isosorbide 5-mononitrate on mortality following acute myocardial infarction: A multicentre study

We have conducted a randomized, double-blind, placebo-controlledmulticentre trial of oral isosorbide 5-mononitrate (ISMN) in360 patients with suspected acute myocardial infarction. Patientswere stratified prior to analysis according to the presenceor absence of left ventricular failure on admission. ISMN causeda significant reduction in systolic and diastolic blood pressureduring the first 12 h. There was no significant effect on heartrate.Overall mortality was 4-9% in the ISMN group compared with40% in controls at 5 days, and 141% compared with 10-5% at 6months (NS). A non-significant reduction in mortality in theISMN group with heart failure (ISMN 7-9%, placebo 12-9%, at5 days) contrasted with a non-significant increase in mortalityin patients without heart failure treated with ISMN (ISMN 4-1%,placebo 2-1%, at 5 days). Lignocaine was used in twice as manypatients in the ISM N group as in placebo group (P<0-0I),both with and without heart failure. Diamorphine usage was similarin the ISMN and control groups.Oral ISMN has similar haemodynamiceffects to intravenous nitroglycerin, and can be of benefitin acute myocardial infarction with heart failure. However,our results question the use of nitrates in acute myocardialinfarction in the absence of heart failure     

Comparison of the effects of molsidomine,nitroglycerin and isosorbide dinitrate on experimentally induced coronary artery thrombosis in the dog

Summary Platelet activation and aggregation in the coronary circulation may be important in the pathogenesis of myocardial ischemia. Molsidomine (M), isosorbide dinitrate (ISDN) and nitroglycerin (NTG) have been found to inhibit platelet aggregationin vitro. In the present study, the activity of these compounds was investigated in a model of coronary artery thrombosisin vivo. Dogs were ancsthetized, thoracotomized, and their heart was exposed. An electrode was inserted into the left circumflex coronary artery and set to rest on the intima. Electrical stimulation (9 V, 150 A) lasted for 6 h. Compounds (each in 2 dose levels) were given as an i.v. infusion starting 30 min after the beginning of the stimulation and lasting for the duration of the experiment. All control (saline-treated) animals underwent thrombotic occlusion of the coronary artery as assessed by flow measurement. On the other hand, 2/8 dogs treated with the lower M dose and 4/8 dogs treated with the higher M dose did not have a coronary occlusion. Neither ISDN nor NTG, at both doses, prevented the coronary occlusion. In control animals thrombus wet weight was 74.43±11.25 mg. M reduced the thrombus weight in a doserelated manner, while ISDN (marginally) and NTG (significantly at the higher dose) increased this parameter. Following the coronary thrombosis, all control animals developed myocardial infarcts as assessed by the tetrazolium technique. Similarly all animals treated with ISDN and with NTG (at both doses) showed infarcts. However, 3/8 M-dogs did not have a myocardial infarction in the lower as well as in the higher dose groups. The hemodynamic changes induced by the 3 compounds were similar in magnitude.Thus M but not ISDN or NTG showed in thisin-vivo study antithrombotic and consequently antiischemic activity.     

普萘洛尔联合5-单硝酸异山梨酯对肝硬化门静脉高压血流动力学参数的影响

目的探讨普萘洛尔联合5-单硝酸异山梨酯治疗对肝硬化门静脉高压患者血流动力学参数的影响。方法 30例肝功能Child-Pugh分级A、B级的肝硬化门静脉高压患者随机分为两组,其中普萘洛尔治疗组15例,普萘洛尔联合5-单硝酸异山梨酯治疗组15例,疗程均为48周。所有患者治疗前后均通过超声多普勒显像仪观察门静脉血流速度(VFP)和门静脉内径(PVD),并计算门静脉充血指数(PCI)。结果普萘洛尔组治疗前后VFP分别为(12.01±1.75)cm/s和(10.80±1.32)cm/s,PVD分别为(20.73±1.58)mm和(19.53±1.41)mm,差异均有统计学意义(P<0.05),PCI未显著下降(P>0.05);联合组治疗前VFP、PVD和PCI分别为(11.40±1.55)cm/s、(20.87±1.50)mm和(0.2940±0.4561),治疗后分别为(9.60±1.30)cm/s、(15.87±1.19)mm和(0.2107±0.4220),差异均有统计学意义(P均<0.05);两组比较治疗后的VFP、PVD和PCI差异均有统计学意义(P均<0.05)。结论普萘洛尔联合5-单硝酸异山梨酯较单用普萘洛尔能更有效地降低肝硬化门静脉高压血流动力学参数,具有预防上消化道出血的作用。     

A comparison of the day-long antianginal effectiveness of nitroglycerin patches with that of three-times-daily isosorbide dinitrate: a double-blind study using dose titration.

Eight men with stable angina, a positive treadmill test, and demonstrated responsiveness to chronic oral isosorbide dinitrate (ISDN) were studied after they had been taking effective doses of ISDN t.i.d. for at least 2 weeks. Exercise tests were performed every 1-2 h until 19.00 hours over one day after the 08.00 hours application of nitroglycerin patches in a previously titrated dose; on another day after the administration of ISDN capsules q5h; and on a third day after placebo patches and capsules. The mean necessary effective patch dose was 125 cm2 (60-220 cm2). The mean exercise duration to angina rose from 271 to 480 s 1 h after nitroglycerin patches (P less than 0.001). Nitroglycerin patches were superior to the placebo throughout the day, but in a declining degree--by 94 s at 19.00 hours (P less than 0.05). ISDN q5h provided peaks of increased walking time to angina 1 h after each dose, but after 3 h exercise time was down to placebo levels. Furthermore, the peaks were of diminishing amplitude: 200 s at 09.00 hours, 150 s at 14.00 hours, but only 70 s at 19.00 hours. Thus, neither nitrate regimen provided continuous near-peak benefit throughout the 11 h period, although nitroglycerin patches had a significantly greater (P less than 0.05) overall effect during the day.     

5-单硝异山梨酯缓释剂治疗老年单纯收缩期高血压疗效观察

目的 观察5-单硝异山梨酯缓释剂（ISMN）对老年单纯收缩期高血压（ISH）患者降压治疗的疗效。方法 80例ISH患者随机分为对照组39例和治疗组41例，对照组给予氨氯地平5mg，吲达帕安2．5mg每日1次口服，治疗组在上述治疗的基础上给予5-单硝异山梨酯缓释剂40mg每日1次口服，疗程4周。结果 （1）治疗组从第一周开始收缩压（SBP）下降幅度即大于对照组，先于对照组于第二周降至正常，差异有显著性（P〈0．05）；（2）从第一周开始治疗组舒张压（DBP）下降幅度即小于对照组（P〈0．05），第三周开始差距加大，差异有非常显著性（P〈0．01），整个观察期内治疗组DBP下降幅度始终小于对照组，且从第二周开始处于相对稳定状态；（3）第一周开始治疗组脉压（PP）下降幅度即大于对照组（P〈0．05），第二周开始差距进一步加大，差异有非常显著性（P〈0．01）。结论 硝酸酯类药物能降低ISH患者的SBP,而对DBP影响不大，使PP减小，对ISH患者降压治疗有益。     

Influence of glyceryl trinitrate on venous and arterial effects of chronic,asymmetric isosorbide dinitrate treatment in patients with ischemic heart disease

Asymmetric dosage regimes have been introduced to circumvent development of nitrate tolerance. This study assessed invasively the hemodynamics during supine rest and exercise before and after 4 weeks treatment with 30 mg isosorbide dinitrate (ISDN) or placebo asymmetrically b.i.d. in 14 randomized patients with stable ischemic heart disease in a double-blinded study. An intravenous infusion of glyceryl trinitrate (GTN) was used to assess possible nitrate tolerance. During the initial, medication-free exercise all patients had increased pulmonary arterial wedge pressure (PAWP) 31.4 ± 5.56 mmHg (mean ± SD), showing impaired left ventricular function, while mean arterial pressures (MAP) rose from 112 ± 16.3 mmHg at rest to 141 ± 15.9 mmHg during exercise. After 4 weeks ISDN treatment, mean exercise PAWP and MAP, 3 h after morning dose, were reduced to 22.4 ± 7.09 mmHg and 127 ± 18.2 mmHg, respectively. Before the ISDN treatment, GTN reduced exercise PAWP to 13.9 ± 5.27 mmHg and MAP to 119 ± 11.2 mmHg, whereas after 4 weeks ISDN treatment, the addition of GTN did not reduce exercise PAWP and MAP to the same low levels. Thus, the applied ISDN regimen improved the hemodynamics, but induced a definite, partial nitrate tolerance.     

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.     

Hemodynamic time course of acute and chronic isosorbide dinitrate treatment at rest and during exercise in patients with stable ischemic heart disease

Hypothesis: The study was undertaken to establish differences between venous and arterial isosorbide dinitrate (ISDN) effects during acute and chronic treatment, hemodynamics at rest, and during supine exercise. Methods: These effects were assessed invasively in 16 patients with stable ischemic heart disease before and at hourly intervals for 4 h after administration of peroral 30 mg ISDN. Eight patients were previously untreated (acute group), and eight were treated with 30 mg ISDN asymmetrically b.i.d. for two weeks (chronic group). Results: Prior to ISDN administration, right atrial, mean pulmonary artery, pulmonary artery wedge, and mean arterial pressure (RAP, MPAP, PAWP, and MAP) rose from normal resting to pathologic values during exercise. One h after ISDN administration, all exercise pressures were normalized (p<0.001). During the following 3 h, exercise RAP rose similarly in both groups (p<0.01), while MPAP rose particularly in the chronic group (p<0.001). Exercise PAWP and MAP, however, remained low in the acute group, but increased markedly in the chronic group (p<0.01), particularly from the third to the fourth hour after ISDN. Conclusion: The daily, asymmetric administration of 30 mg ISDN b.i.d. maintained beneficial, anti-ischemic effects for 2 to 3 h after a morning dose of the drug, but thereafter attenuation of the effects occurred in the arteries but not in the veins.     

Acute and chronic effects of isosorbide-5-mononitrate administration on effective renal plasma flow and the renin-aldosterone system in cirrhotic patients

BACKGROUND AND AIMS: Isosorbide-5-mononitrate (ISMO) has been shown to be effective in reducing the risk of variceal bleeding in patients with cirrhosis. However, recent studies have suggested that this drug compromises renal function. The present study was conducted to assess the acute and chronic effects of ISMO on effective renal plasma flow (ERPF) and the renin-aldosterone profile in cirrhotic patients. METHODS: Fifteen cirrhotic patients were included in the present study. The mean arterial pressure (MAP), heart rate (HR), serum renin concentration (SR), ERPF and plasma aldosterone concentration (PA) were checked before ISMO treatment (baseline study), after a single oral dose of 20 mg ISMO (acute effect study) and after 3 weeks of ISMO treatment (chronic effect study). RESULTS: Our data showed that the oral administration of a single dose (20 mg) of ISMO to cirrhotic patients was associated with significant decreases in ERPF (from 405.18 to 369.06 mL/min) and MAP (from 93.26 to 86.40 mmHg), and increases in HR (from 65.53 to 70.06 beats/min), SR (from 24.15 to 54.41 pg/mL), and PA (from 105.1 to 148.7 pg/mL). However, no significant changes were observed in HR, MAP, PA, SR, or ERPF after 3 weeks of ISMO treatment when compared with the baseline study. CONCLUSIONS: The administration of ISMO causes a decrease in ERPF in cirrhotic patients and its use in patients with renal impairment should be considered cautiously.     

Somatostatin plus isosorbide 5-mononitrate versus somatostatin in the control of acute gastro-oesophageal variceal bleeding: a double blind, randomised, placebo controlled clinical trial

BACKGROUND: Variceal bleeding is a severe complication of portal hypertension. Somatostatin reduces portal pressure by decreasing splanchnic blood flow, and nitrates by diminishing intrahepatic resistance. Experimental studies have shown that the combination of somatostatin and nitrates has an additive effect in decreasing portal pressure. AIM: To compare the therapeutic efficacy of either intravenous infusion of somatostatin plus oral isosorbide 5-mononitrate or somatostatin alone in gastro-oesophageal variceal bleeding associated with liver cirrhosis. METHODS: A unicentre, double blind, placebo controlled, clinical trial was conducted. Sixty patients bleeding from oesophageal or gastric varices were randomised to receive intravenous infusion of somatostatin (250 microg/hour) plus oral isosorbide 5-mononitrate (40 mg/12 hours) (group I) or somatostatin infusion plus placebo (group II) for 72 hours. RESULTS: The two groups of patients had similar clinical, endoscopic, and haematological characteristics. Control of bleeding was achieved in 18 out of 30 patients (60%) in group I and 26 out of 30 patients (87%) in group II (p<0.05). There was no significant difference in mean transfusion requirements between the two groups: 2.6 (2.2) v 1.8 (1.6) respectively; means (SD). Mortality and side effects were similar in the two groups, but development of ascites was higher in group I (30%) than in group II (7%) (p<0.05). CONCLUSION: In cirrhotic patients with acute gastro-oesophageal variceal bleeding, addition of isosorbide 5-mononitrate to somatostatin does not improve therapeutic efficacy, induces more adverse effects, and should not be used.     

Mechanisms of nitrate tolerance

Summary There is now little dispute that clinical tolerance of organic nitrates occurs, particularly when these drugs are used by themselves to treat patients with stable angina pectoris and congestive heart failure. Classical hypotheses of nitrate tolerance suggest the phenomenon to result from vascular depletion of critical sulfhydryl groups, which are necessary to bring about vasorelaxation from nitrates. While this mechanism of nitrate tolerance probably operates when isolated blood vessels are exposed to high concentrations of nitrate in vitro, there is little evidence to suggest that it contributes to clinical nitrate tolerance. Instead, emerging data suggest that nitrates can cause significant shifts in fluid distribution and secretion of neurohormonal factors that can modulate their vasorelaxant effects. use of angiotensin converting enzyme inhibitors and diuretics in conjunction with nitrates may alleviate the development of tolerance, but the experience has not been universally favorable. Other receptor-effector systems that affect cardiovascular function, such as the adrenergic system, may also be affected by nitrate tolerance. The mechanisms of nitrate tolerance are therefore likely to be multifactorial, involving vascular biochemical changes, physiologic compensation, and possibly receptor regulation.     

Response to changing plasma concentrations of isosorbide-bound NO2 during acute and sustained treatment with isosorbide dinitrate in patients with coronary artery disease

BACKGROUND: The mechanisms behind development of tolerance to nitrate effects during sustained, asymmetric isosorbide dinitrate (ISDN) therapy are not fully understood. HYPOTHESIS: The study was undertaken to investigate the changes of the relationships between left ventricular (LV) function and plasma concentrations of ISDN and its vasoactive metabolites (2- and 5-ISMO) during acute and sustained, asymmetric ISDN therapy. METHODS: Left ventricular function and plasma concentrations of ISDN, 2- and 5-isosorbide mononitrates (P-ISDN, P-2- and 5-ISMO) were measured at rest and at supine exercise before and for 4 h after peroral 30 mg ISDN in 15 patients with coronary artery disease, all with initial exercise pulmonary artery wedge pressure (PAWP) > 25 mmHg. Seven patients were untreated (acute group), while eight received 30 mg ISDN b.i.d. for 2 weeks before the invasive study. P-ISDN and the concentration of available isosorbide-bound nitrate (NO2) in plasma (P-ISDN.2 + P-2-ISMO + P-5-ISMO) (P-NO2) were used as measures of the nitric oxide (NO) offer to the tissues. RESULTS: Throughout the study, after administration of medication, all plasma concentrations, in particular P-ISDN, were higher in the chronic than in the acute group. Peak P-ISDN was reached after 15 min in the chronic group and after 25 min in the acute group, while P-2- and 5-ISMO reached maximum only after 40 min in both groups. At rest, the full effect on PAWP was observed after 10 min in both groups, but at markedly higher levels of P-ISDN and P-NO2 in the chronic group. Afterward, no further changes in PAWP were observed. During exercise, 1 h after medication, PAWP and stroke index to PAWP ratio (SI/PAWP) were normal in both groups. Thereafter, at slowly declining P-NO2, PAWP rose and SI/PAWP declined toward the initial level in the chronic group, but remained unchanged in the acute group, in spite of higher P-NO2 and greater NO release in the former. CONCLUSIONS: Patients receiving sustained, asymmetric 30 mg ISDN b.i.d. dosing had the same immediate beneficial effects on LV function during exercise after a morning dose as did untreated patients. However, in spite of higher P-NO2 and higher rate of NO release during sustained treatment, the effects deteriorated gradually 2 to 3 h after medication. The changes in metabolism and/or distribution of isosorbide-bound NO2 may possibly be part of the tolerance induced by long-term treatment, even with asymmetric dosing.     

Hemodynamic action of captopril in coronary patients with heart failure tolerant to nitroglycerin

Background: At present there is little dispute that clinical tolerance of organic nitrates occurs during long-term treatment of patients with stable angina pectoris and congestive heart failure. Hypothesis: Captopril exerts a favorable hemodynamic effect in coronary patients with heart failure who are clinically tolerant to nitroglycerin. Methods: Development of nitrate tolerance was observed during intravenous nitroglycerin treatment (10 mg/h) in 16 of 19 patients (7 women, 12 men; mean age 56 ± 8 years) with coronary heart disease [stenosis ≥ 75%, New York Heart Association (NYHA) classes II–III). The criterion applied was a loss of efficacy of at least 50% with regard to mean pulmonary capillary wedge pressure compared with the maximum effect of nitrate. The effect of captopril (50 mg p.o.) was determined in a blank test. Captopril (50 mg p.o.) was administered again at the stage of clinically manifest nitrate tolerance. Results: Compared with the effect of captopril alone, significantly more pronounced reductions in mean pulmonary capillary wedge pressure (33% compared with 27%) and in mean pulmonary arterial pressure (36% compared with 17%) and significantly greater increases in cardiac index (14% compared with 7%) and stroke work index (34% compared with 18%) (p < 0.05 in each case; Wilcoxon test for linked random samples) were measured. Maintaining nitroglycerin infusion, the effect of captopril (at least 90% of the maximum effect) lasted for 123 ± 24 min. The baseline values (at least 75% decline in the effect of captopril) were only reached after 369 ± 34 min. Conclusion: The results document a favorable hemodynamic effect of captopril in nitrate tolerance which is significantly better than that of captopril alone.     

In Vivo Cardioprotection by N-Acetylcysteine and Isosorbide 5-Mononitrate in a Rat Model of Ischemia-Reperfusion

Aims: We evaluated the effect of N-acetylcysteine (NAC, infused i.v.), isosorbide 5-mononitrate (IS5MN, by gavage), or their combination on cardiac injury in an in vivo rat model of 30-min ischemia followed by 24 hours or 7 days of reperfusion. Results: When administered immediately prior to reperfusion with continuous infusion for 24 h, the combination of NAC + IS5MN reduced infarct size (29 ± 6 vs. 59 ± 4% area-at-risk, p < 0.01) and the infiltration of polymorphonuclear leukocytes (226 ± 15 vs. 315 ± 18 cells mm^–2 of area-at-risk, p = 0.002) and monocytes/macrophages (118 ± 8 vs. 194 ± 22 cells mm^–2, p = 0.012), compared to vehicle. NAC or IS5MN alone did not reduce infarct size at 24 hours of reperfusion. The same dose regimen of NAC and IS5MN did not reduce infarct size with permanent ischemia for 24 hours not followed by reperfusion. After 7 days of reperfusion (3 days of treatment with NAC + IS5MN or vehicle and 4 days of wash-out), infarct size was similar in the vehicle and NAC + IS5MN groups, but LV end-diastolic pressure and diastolic LV chamber wall stress were significantly lower in the animals treated with NAC + IS5MN (5 ± 1 mmHg and 62 ± 7 dyne mm^–2, respectively) compared to vehicle (9 ± 1 mmHg and 123 ± 18 dyne mm^–2, p < 0.05). Conclusion: We demonstrate in a rat model of cardiac ischemia-reperfusion treated with NAC and IS5MN, according to a regimen that mimicked a clinical situation (drugs started at time of reperfusion), that the short-term benefit seen after 24 h of reperfusion (51% reduction of infarct size) is maintained after one week, possibly through modulation of the inflammatory response to cardiac injury.     

Once- versus twice-daily administration of controlled-release isosorbide-5-mononitrate 60 mg in the treatment of stable angina pectoris: A randomized, double-blind, cross-over study

Thirty-seven patients with chronic, stable angina pectoris wereincluded in a randomized, double-blind cross-over study to assessthe efficacy of once- and twice-daily dosage regimens of 60mg isosorbide-5-mononitrate, in a controlied release formulation(5-ISMN Durules^® Astra). After 2 weeks of treatment, duringa symptom-limited bicycle ergometer exercise test performed3 h after the dose, the time to 1 mm ST segment depression wasobserved to be longer by once-daily than by a twice-daily dosageregimen (614 ± 165 vs 561 ± 148 s, P<0·01).The time to the end of exercise was also significantly prolongedby once-daily dosage, as compared with placebo (693 ±158 and 645 ± 173 s, respectively; P<0·05),which was not observed with the twice-daily regimen. Both dosageregimens still had a significant effect on the prolongationof the time to onset of angina 9 h after the dose: 420 ±164 s by placebo, 492 ± 161 s by once-daily dosage; P<0·01and 466 ± 154 s by twice-daily dosage; P<0·05.Anginal attack rate and nitroglycerin consumption was significantlylower during the once-daily dosage period as compared with placebo;this difference was not evident during the twice-daily administrationof the drug. Controlled-release 5-ISMN 60 mg given once daily was effectivein angina pectoris patients for at least 9 h after the doseand showed no clinical signs of tolerance after 2 weeks of thetreatment. Attenuation of the clinical effect was observed withthe twice-daily (in 12 h intervals) dosage regimen, presumablycaused by constantly high 5-ISMN plasma concentration.