Dose-ranging study of isosorbide-5-mononitrate in chronic congestive heart failure treated with diuretics and angiotensin-converting enzyme inhibitor

The hemodynamic response of isosorbide-5-mononitrate (IS-5-MN) to the addition of the widely used therapy of diuretic drugs and the maximally tolerated dose of enalapril for heart failure was assessed in 8 patients with congestive heart failure (CHF) (New York Heart Association class II and III). The diuretic therapy was furosemide, 40 to 80 mg/day, with or without amiloride, 5 to 10 mg/day. The dose of enalapril was 5 to 20 mg/day. Four hours after the administration of the morning dose of enalapril, a Swan-Ganz catheter was positioned in the pulmonary artery. Patients received increasing doses of IS-5-MN to produce a satisfactory decrease in pulmonary capillary wedge pressure. Two of the first 3 patients studied had a large reduction in blood pressure when given 10 mg of IS-5-MN. Subsequent patients were therefore given an initial dose of 5 mg, the total dose being 5 to 20 mg over 2 hours. Results at baseline and 1 hour after the final dose of IS-5-MN are expressed as mean +/- standard deviation. Both pulmonary artery systolic and diastolic pressures decreased significantly (p less than 0.05) by 12.2 +/- 8.9/4.2 +/- 5.2 mm Hg, from 47.2 +/- 16.0/21.6 +/- 6.0 mm Hg to 35.0 +/- 15.2/17.4 +/- 9.3 mm Hg. Pulmonary capillary wedge pressure decreased by 8.6 +/- 4.4 mm Hg, from 22.1 +/- 5.4 to 13.6 +/- 7.5 mm Hg (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of oral isosorbide-5-mononitrate and dinitrate in ischemic heart failure

Isosorbide-5-mononitrate (ISMN), the main metabolite of isosorbide dinitrate (ISDN) was recently introduced in clinical use. The hemodynamic effects of oral ISMN and ISDN, administered in equal doses, were studied in a randomized, crossover fashion in 20 patients with pump failure of ischemic etiology. Baseline hemodynamic criteria for admission into the study were: pulmonary capillary wedge pressure (PCW) of at least 20 mmHg and systolic arterial pressure (AP) above 90 mmHg. Hemodynamic parameters were serially measured and systemic vascular resistance was calculated up to 6 h postadministration of either ISMN or ISDN single dose (40 mg). Maximal effects obtained were statistically significantly different from baseline. While ISMN and ISDN appeared to be equipotent in reducing the filling pressure, with a maximum effect reached in 60-120 min, the mononitrate maintained its effects for a longer period.     

Hemodynamic effects of intermittent transdermal nitroglycerin in chronic congestive heart failure

The hemodynamic effects of intermittent and continuous treatment with transdermal nitroglycerin, 10 mg/24 hours, were compared in 10 patients with chronic congestive heart failure (CHF). Eight patients responded to initial application with more than a 20% reduction in mean pulmonary artery wedge pressure. Cardiac index increased from a control value of 2.1 +/- 0.5 to 2.4 +/- 0.6 liters/min/m2 at 2 hours (p less than 0.05) and mean pulmonary wedge pressure was reduced from 22 +/- 5 to 16 +/- 6 mm Hg (p less than 0.01). The 2 nonresponders had the largest left ventricular volumes on 2-dimensional echocardiograms. Responders were randomized to intermittent (16 hours/day) or continuous (24 hours/day) treatment for 1 month followed by a month of the alternate treatment. After 1 month of intermittent treatment, the hemodynamic response after reapplication was similar to the initial response. After another month of continuous treatment, hemodynamic values 24 hours after application were similar to initial control values and there was no change after removal and reapplication. Thus, the moderate vasodilator effect of transdermal nitroglycerin in CHF is maintained with intermittent treatment, whereas tolerance develops with continuous treatment.     

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.     

Acute and chronic effects of sustained action buccal nitroglycerin in severe congestive heart failure

Vasodilators, such as nitroglycerin, have been widely used in the treatment of acute and chronic heart failure for therapeutic manipulation of the venous and arterial circulations to improve left ventricular function. We have tested the efficacy of a new formulation for sustained release buccal delivery of nitroglycerin (biological life 5-6 hr) in 21 patients with severe congestive heart failure due to ischaemic cardiomyopathy using maximal treadmill exercise testing and radionuclide angiography. A single-blind placebo-controlled acute and an open chronic phase (4 weeks) of treatment were employed. The mean dose was 23.4 mg daily, and clinical assessment suggested significant improvement in 15 patients. The mean ejection fraction (placebo) of 14.1% +/- 1.6 SEM increased to 19.1% +/- 1.7 (acute) and to 21.6% +/- 1.7 (chronic treatment) (P less than 0.001; n = 16). The mean exercise time increased from 3.02 +/- 0.4 min (basal) to 5.95 +/- 0.6 min (chronic) (P less than 0.001). Segmental wall motion abnormality was shown to improve after treatment for 4 weeks. There were no major side effects. Nine patients were reassessed after 24 weeks on the same regimen; exercise time and left ventricular ejection fraction were similar to the 4-week period, thus demonstrating a sustained improvement in cardiac function and functional capacity. A worthwhile functional and objective haemodynamic improvement was demonstrated in these patients with severe chronic congestive heart failure. This mode of treatment may have useful therapeutic value in the management of patients with a wide range of ischaemic heart failure.     

单硝酸异山梨醇酯致老年低血压的临床分析

目的对单硝酸异山梨醇酯缓释片导致老年低血压进行分析,以便更好的进行防治。方法对8例因鼻饲单硝酸异山梨醇酯缓释片后,导致低血压状态的老年患者的临床特点、救治情况进行分析,并与同期相同方式用药未出现低血压的9例患者进行对比分析。结果 8例患者均为60 mg/日,用药后出现低血压,6例患者使用多巴胺升压、扩容等综合治疗后好转,严重1例并发急性心肌梗死及急性肾功能衰竭,经机械通气等抢救好转。与非低血压组比较,病情不稳定、单硝酸异山梨醇酯用药剂量大、时间长、并用降压药物、近期鼻饲给药比例较高,差异有统计学意义(P0.05)。结论高龄老年患者尤其是病情不稳定、并用降压药物、近期鼻饲使用高剂量单硝酸异山梨醇酯缓释片容易出现低血压,甚至可导致严重并发症。     

Pharmacokinetic-hemodynamic studies of nitroglycerin ointment in congestive heart failure

The aim of this study was to determine the bioavailability of nitroglycerin after application of nitroglycerin ointment in patients with heart failure and to examine whether a correlation exists between plasma nitroglycerin and its hemodynamic effects. The dose of nitroglycerin ointment selected was based on the prior hemodynamic response of individual patients to an intravenous infusion of nitroglycerin. Nine patients received 1 to 2 inches of nitroglycerin ointment on a single skin site (small dose group) and five patients received 4 inches (2 inches to two separate skin sites, large dose group).There was good correlation between the dose of nitroglycerin ointment and bioavailability (area under the plasma concentration time curve from 0 to 240 minutes) (r = 0.81, p < 0.001). We observed a decrease in both pulmonary capillary wedge pressure and right atrial pressure 30 minutes after application of nitroglycerin ointment. The maximal changes in pulmonary capillary wedge pressure were from 28 ± 7 to 23 ± 8 mm Hg and in right atrial pressure from 14 ±7 to 11 ±6 mm Hg. There was a greater decrease in pulmonary capillary wedge pressure in the small dose group (31 percent) compared with the large dose group (13 percent) (p < 0.001). Plasma nitroglycerin concentration in the small dose group increased to 3.1 ± 3.0 ng/ml at 60 minutes and remained at that level through 240 minutes. In the large dose group a plasma nitroglycerin level of 8.9 ± 4.0 ng/ml was achieved at 60 minutes and sustained through 240 minutes. Despite this plasma nitroglycerin level there was little decline in pulmonary capillary wedge pressure. This study demonstrates a good relation between the dose of nitroglycerin ointment and nitroglycerin bioavailability; nitroglycerin ointment also provides therapeutic levels of nitroglycerin associated with substantial hemodynamic benefit in selected patients with cardiac failure.     

Hemodynamic effects of nitroglycerin ointment in congestive heart failure

The hemodynamic effects of nitroglycerin absorbed transcutaneously from an ointment base were determined in 10 patients with chronic congestive heart failure (9 with ischemic heart disease and 1 with cardiomyopathy). The response was characterized by a decrease in pulmonary capillary wedge pressure from an average of 30 to 19 mm Hg, and an increase in cardiac index from 1.7 to 2.2 liters/min per m², with concomitant decreases in systemic and pulmonary vascular resistance and an increase in venous capacitance. Mean arterial pressure decreased from 85 to 80 mm Hg, and heart rate remained unchanged. The hemodynamic effects persisted for 3 to 6 hours. These results indicate that nitroglycerin ointment is a hemodynamically potent vasodilating agent with potential value in the therapy of congestive heart failure.     

Pharmacokinetic-hemodynamic studies of transdermal nitroglycerin in congestive heart failure

Ten patients with chronic congestive heart failure were studied to assess the hemodynamic effects and bioavailability of a transdermal nitroglycerin delivery system. Nitrate sensitivity was defined by a prior 20 minute infusion of nitroglycerin, 21 micrograms/min. Five patients with a satisfactory hemodynamic response to intravenous nitroglycerin received two nitroglycerin patches of 10 cm2 each and five patients who did not achieve a satisfactory response to intravenous nitroglycerin (that is, greater than or equal to 25% reduction in left ventricular filling pressure) received larger doses of transdermal nitroglycerin. In the five nitrate-sensitive patients who received 20 cm2 of transdermal nitroglycerin, one study was terminated at 90 minutes, at which point there was no detectable hemodynamic response or arterial plasma nitroglycerin evident. Two patients had a minimal hemodynamic response and a peak plasma concentration of 1 ng/ml. A fourth patient had a short-lived hemodynamic response at 60 and 120 minutes and a plasma nitroglycerin concentration of 1 ng/ml at 60 minutes. A fifth patient had a hemodynamic response persisting for 24 hours and plasma concentrations between 0.6 and 1.1 ng/ml. The remaining five patients showed little or no hemodynamic response despite doses of transdermal nitroglycerin from 40 to 60 cm2. The highest plasma concentration achieved in these patients was 2 ng/ml and there was no relation between dose administered and plasma concentration achieved. In 4 of the 10 patients who subsequently received nitroglycerin ointment, there were a greater decrease in left- and right-sided filling pressures and greater increase in plasma nitroglycerin concentrations (from 1.6 to 4.8 ng/ml) than those that occurred with transdermal nitroglycerin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic and hormonal effects of high-dose transdermal nitroglycerin in patients with chronic congestive heart failure

The hemodynamic effect of a large dose of nitroglycerin (NTG) (90 mg) given transdermally using a reservoir system was studied in 10 patients with severe, long-standing congestive heart failure. Serial hemodynamic measurements over 24 hours revealed a mild decrease in mean pulmonary artery wedge pressure. However, the change from baseline was significant only at 2 hours (19 +/- 9 vs 27 +/- 6 mm Hg). Mean right atrial pressure fell 1 hour after initiation of therapy, from 12 +/- 7 to 8 +/- 5 mm Hg. However, the change from control was not statistically significant. No significant changes were noted in heart rate, mean blood pressure, cardiac index, and systemic and pulmonary vascular resistance. Individual analysis of the effect of transdermal NTG on pulmonary artery wedge pressure demonstrated at 20% or greater reduction in 8 of 10 patients. However, persistent effect (longer than 8 hours) was seen in only 4 patients. Removal of NTG patches at 24 hours did not result in hemodynamic rebound. Serum catecholamine levels and renin concentration did not change 2 hours and 24 hours after initiation of NTG therapy or after removal of NTG patches. Thus, a large dose (90 mg) of transdermal NTG using a reservoir system results in mild and mostly statistically insignificant hemodynamic effect in patients with chronic severe congestive heart failure. Although a reduction in pulmonary artery wedge pressure is seen in most patients, rapid attenuation of this response is found in many patients and the effect only rarely lasts for 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic factors limiting the response to transdermal nitroglycerin in severe chronic congestive heart failure

To clarify the continuing controversy concerning the use of transdermal nitroglycerin (TDN), the shortterm hemodynamic responses to sublingual, oral and transcutaneous nitrates were evaluated and compared in 22 patients with severe chronic congestive heart failure. Sixteen patients showed favorable hemodynamic effects with TDN, but the doses needed to achieve this response varied greatly: 10 mg/24 hours in 6 patients, 20 mg/24 hours in 5 patients, 40 mg/24 hours in 3 patients and 60 mg/24 hours in 2 patients. Of the 6 remaining patients, 3 did not respond to high-dose TDN even though they showed marked effects after sublingual and oral nitrate administration; 3 others did not respond to any nitrate formulation by any route. TDN produced immediate increases in cardiac index and decreases in right and left ventricular filling pressure, mean arterial pressure and systemic vascular resistance (p less than 0.01). These effects, however, became rapidly attenuated within 3 to 6 hours; after 18 to 24 hours, only modest decreases in right and left ventricular filling pressures were observed. After removal of TDN treatment, rebound decreases in cardiac index and rebound increases in mean arterial pressure and systemic vascular resistance occurred, but right and left ventricular filling pressures returned to pretreatment values without rebound changes. Isosorbide dinitrate, 40 mg orally, produced hemodynamic effects that were greater in magnitude than effects seen after administration of TDN (p less than 0.05 to 0.01), but 4 patients in whom tolerance to TDN developed showed reversible cross tolerance to oral isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparative evaluation of hemodynamic and neurohumoral effects of nitroglycerin and nifedipine in congestive heart failure

Nitroglycerin and nifedipine have been suggested as useful agents in the therapy of congestive heart failure. Because of the rapid action and feasability for sublingual administration of both drugs, their comparative hemodynamic and neurohumoral effects were studied in 12 patients with congestive heart failure. After sublingual nitroglycerin, there was a significant decrease in mean arterial pressure (96 +/- 17 to 90 +/- 15 mm Hg, p less than 0.01), left ventricular (LV) filling pressure (30 +/- 12 to 22 +/- 10 mm Hg, p less than 0.01), right atrial pressure (15 +/- 6 to 10 +/- 5 mm Hg, p less than 0.01) and systemic vascular resistance (21.5 +/- 7.7 to 19.3 +/- 6.2 units, p less than 0.05) and an increase in cardiac index (2.2 +/- 0.6 to 2.4 +/- 0.7 liters/min/m2, p less than 0.05) and LV stroke work index (20.4 +/- 7.0 to 24.5 +/- 8.6 gm-m/m2, p less than 0.01). After sublingual nifedipine, there was also a significant decrease in mean arterial pressure (96 +/- 16 to 89 +/- 14 mm Hg, p less than 0.01) and systemic vascular resistance (22.1 +/- 7.1 to 18.0 +/- 6.1 units, p less than 0.01) and an increase in cardiac index (2.1 +/- 0.6 to 2.4 +/- 0.6 liters/min/m2, p less than 0.01); in contrast to nitroglycerin, this was unaccompanied by significant changes in right- or left-sided filling pressures or LV stroke work index.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined hemodynamic effects of nifedipine and nitroglycerin in congestive heart failure

To determine if the addition of preload reduction with nitrates would potentiate the acute vasodilator actions of nifedipine, we titered intravenous nitroglycerin in seven patients with severe congestive heart failure after they received a single oral dose of nifedipine. The peak hemodynamic effect of nifedipine occurred at 30 minutes, with large reductions of systemic vascular resistance (1831 +/- 128 to 1132 +/- 154 dynes X sec X cm-5; p less than 0.001) and mean arterial pressure (87 +/- 7 to 71 +/- 7 mm Hg; p less than 0.01). This was associated with an increase of stroke volume index from 22 +/- 3 to 27 +/- 3 ml/m2 (p less than 0.01) but no significant changes in heart rate, right atrial pressure, or pulmonary wedge pressure. These hemodynamic changes were attenuated over a 2-hour observation period. At 2 hours, the addition of intravenous nitroglycerin resulted in large reductions in right atrial pressure (9 +/- 2 to 6 +/- 1; p less than 0.01) and pulmonary wedge pressure (23 +/- 2 to 17 +/- 2; p less than 0.001). This was associated with further increases in cardiac index (from 1.99 +/- .15 to 2.25 +/- .14 L/min/m2; p less than 0.001) and stroke volume index (26 +/- 3 to 29 +/- 3 ml/m2; p less than 0.01). Thus, the addition of nitroglycerin to nifedipine will optimize preload reduction and enhance the vasodilator action of nifedipine. Further controlled studies are necessary to determine the long-term hemodynamic effects and the clinical role of nifedipine and its combination with nitrates in patients with severe congestive heart failure.     

Use of nitroglycerin ointment in congestive heart failure. Results of acute and chronic therapy.

7 consecutive patients with congestive heart failure refractory to standard therapy were treated with nitroglycerin ointment (GTNO). The pulmonary wedge pressure decreased from a control value of 30+/-1 to 15+/-1 mm Hg (mean +/-SEM), and the arteriovenous oxygen difference narrowed from 6.8+/-0.5 to 5.5+/-0.3 ml%, after GTNO therapy. The heart rate decreased in 5 patients and the systolic blood pressure was either unchanged or decreased slightly. A reduction in the echocardiographic end diastolic dimension was noted in all patients. The transmyocardial gradient (systemic artery diastolic pressure - pulmonary artery wedge pressure) increased in all except 1 subject. The double product decreased in 5 of the 7 patients. Hemodynamic improvement was maintained for 4.5-7 h. All patients were symptomatically improved on chronic GTNO treatment. Our results indicate that GTNO is a useful agent in the management of heart failure which is unresponsive to standard therapy.     

A new antianginal preparation: isosorbide-5-mononitrate

Repeated treadmill exercise tests were used in 20 patients with stable exercise-induced angina in order to comparatively examine various dosage forms of isosorbide-5-mononitrate (IMN) and isosorbide dinitrate (ID) during their single administration. The antianginal effect of conventional IMN tablets (Monisid, Bulgaria) lasted about 5 hours and 1-2 hours longer than that shown by long-acting tablets (Olicard, FRG) and lasted on an average of 12 hours. There was a correlation between the antianginal effect of IMN and its blood concentration. A significant individual variability was observed in the potency of all the dosage forms of IMN and ID under study. The dosage form of IMN had antianginal effects that were similar and even superior to those exhibited by ID.     

The altered baroreceptor response to nitroglycerin in congestive heart failure

The use of nitroglycerin as a vasodilator in the treatment of congestive heart failure has demonstrated that the hemodynamic response is related to the degree of left ventricular dysfunction. Little emphasis has been placed on the mechanisms responsible for the variability in heart rate response to nitroglycerin. To study this problem, 33 patients with a variety of chronic cardiac disorders were given 0.4 mg of nitroglycerin sublingually. An increase in heart rate of <3 beats/min to sublingual nitroglycerin allowed a clear identification of a group of patients who had a left ventricular end-diastolic pressure >18 mmHg or pulmonary artery mean pressure >22 mmHg, and who had improvement in hemodynamic parameters following nitroglycerin. This alteration in baroreceptor sensitivity appears to be related to the level of left ventricular filling pressure, and can be used as a simple bedside means of identifying a group of patients who benefit the most from the vasodilator action of nitroglycerin.     

Rapidly developing tolerance to transdermal nitroglycerin in congestive heart failure

We have reported early attenuation of hemodynamic effects of transdermal nitroglycerin in patients with heart failure. We now report nitroglycerin plasma levels in those same patients. We administered transdermal nitroglycerin, 60 mg/24 h, to eight patients or placebo to seven patients in a double-blind fashion, and monitored pulmonary wedge pressure and nitroglycerin plasma levels for 24 hours. After placebo administration, nitroglycerin plasma levels and pulmonary wedge pressure remained unchanged. During transdermal nitroglycerin administration, the plasma nitroglycerin level rose from 0.04 +/- 0.12 ng/mL at baseline to near peak levels at 2 hours (7.43 +/- 7.21 ng/mL). Between 2 and 24 hours, levels fluctuated at a steady state. Pulmonary wedge pressure fell from 22 +/- 7 mm Hg at control to a nadir of 14 +/- 5 mm Hg at 4 hours (p less than 0.01). Despite persistently high plasma nitroglycerin levels, by 18 hours pulmonary wedge pressure was no longer significantly reduced (20 +/- 9 mm Hg). These results indicate that rapid development of tolerance is the cause of attenuated hemodynamic efficacy of transdermal nitroglycerin.     

Comparison of the clinical and hemodynamic effects of nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate in acute myocardial infarction]

One hundred and eighty patients with acute myocardial infarction (MI) were followed up. The patients were divided into 3 groups: (1) those receiving glyceryl trinitrate (GTN) (n = 43); (2) those on isosorbide dinitrate (ISDN) (n = 66); (3) those on isosorbide-5-mononitrate (IS-5-MN) (n = 71). In all the groups, the drugs were given by long-term continuous oligovolumic infusion. Following 24 hours of administration, 66.7, 47.3, and 17.1% increases in infusion rates were required in 74.4, 72.7, and 26.8% of the patients from Groups 1, 2, and 3, respectively. All the agents produced a pronounced antianginal effect and resulted in alleviated acute left ventricular failure. The in-hospital mortality rates were 16.2, 16.7, and 12.7% in Groups 1, 2, and 3, respectively. GTN, ISDN, and IS-5-MN caused adverse effects in 4.7, 18.2, and 2.8% of the patients from Groups 1, 2, and 3, respectively.