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PubMed1996

Therapeutic effects of nitric oxide-donor isosorbide dinitrate on atherosclerosis-induced alterations in hemodynamics and arterial viscoelasticity are independent of the wall elastic component.

Whether the arterial elastic structures are involved in the beneficial effects of long-term treatment with organic nitrates on atherosclerosis-induced changes in hemodynamics and arterial wall viscoelastic properties, are case for angiotensin-converting enzyme (ACE) inhibitors, is not known. In the present study, atherogenic (A) diet, and isosorbide dinitrate (ISDN) (I) (60 mg Risordan LP, daily dose) were given concomitantly for 4 months to adult Pitman-Moore minipigs (A + I animals, n = 8), which were compared with A (n = 8) or control (C, n = 8) animals. Blood flow was investigated by hemodynamics in the hindlimb arterial bed; and wall rheology, histomorphometry and elastin; and desmosine (DES) and isodesmosine (IDE) contents in the abdominal aorta. Atherosclerosis prominently impaired the function of capacitance and resistance arteries, altered blood pressure contours, increased aortic stiffness and wall tension, and reduced parietal viscoelasticity through viscous component blunting. The treatment with ISDN significantly improved aortic pulsatility, arteriolar opposition to blood flow, and blood pressure (BP) contours by restoring, at least in part, the wall viscoelastic properties. However, there was no significant change in the area of the pressure-diameter curve hysteresis between the three animal groups. In contrast, ISDN reduced neither the cross-sectional area of lesions nor the losses in wall elastin content and had no influence on lipid accumulations in vessels and in the blood. The present results demonstrate that the beneficial hemodynamic and wall viscoelastic effects elicited by ISDN in atherosclerotic minipigs are not accounted for by therapeutic properties of the nitric oxide (NO) donor against alterations of elastic structures, but by the viscoelastic properties in the arterial wall.

Animals↗
PubMed1998

Infusions with molsidomine and isosorbide-5-mononitrate in congestive heart failure: mechanisms underlying attenuation of effects.

The use of nitrates for treatment of heart failure is encumbered by tolerance, caused by whatever mechanism, which has been reported only in a few instances with sydnonimines. Accordingly, we compared molsidomine (6 mg/h) and isosorbide-5-mononitrate (3.75 mg/h) with respect to maximal hemodynamic effects, rapidity and extent of attenuation, and underlying mechanisms by means of constant infusions over 24 h each in 15 patients with chronic congestive heart failure (NYHA II-III) with a placebo-controlled, double-blind, randomized, crossover protocol. Hemodynamic measurements and determinations of neurohormones were performed at baseline and at 2, 8, and 24 h after the beginning of infusions. With molsidomine, reductions of diastolic pulmonary artery pressure by 29% (p < 0.001), by 24% (p < 0.01), and by 24% (p < 0.01) versus placebo were found at 2, 8, and 24 h, which amounted to 19% (p < 0.01), 10% (NS), and 14% (NS) with the nitrate. Cardiac output was meaningfully affected only with molsidomine (+5%, NS, at 2 h; +9%, p < 0.05, at 8 h; and +15%, p < 0.05, at 24 h), as was systemic vascular resistance (-13%, p < 0.05; -9%, NS; and -18%, p < 0.01) at the corresponding times. Increases in renin activity amounted to 130% (p < 0.001), 117% (p < 0.001), and 112% (p < 0.001) with molsidomine, and to 14, 16%, and 0 (each NS) with the nitrate at the corresponding times. Hematocrit was reduced by 5% (p < 0.001), 7% (p < 0.001), and 12% (p < 0.01) with molsidomine and by 5% (NS), 5% (p < 0.05), and 5% (NS) with the nitrate. We conclude that neurohumoral counterregulation or fluid shift, which is even more pronounced with molsidomine despite longer-lasting effects, has no essential role in nitrate-tolerance development. With molsidomine, such a role cannot be ruled out, although alternatively, a fluid shift from arterial to the low-pressure arm of circulation during the later course of infusion would be even more likely.

Adult↗
PubMed2000

Echo-dipyridamole stress test evaluation of isosorbide-5-mononitrate efficacy and tolerance in patients with coronary heart disease: interplay with sympathetic activity.

In 22 patients with stable myocardial ischemia, we prospectively studied the short- and long-term effects of isosorbide-5-mononitrate (5-ISMN) on dipyridamole-induced myocardial ischemia, the ability of dipyridamole-stress echocardiography to evaluate nitrate tolerance, and the role of activation of the neurohumoral system in nitrate tolerance development, assessed by modifications of catecholamines plasma levels and heart rate variability. After brief treatment with 5-ISMN, dipyridamole-stress echocardiography was negative in 19 of 22 patients (p < 0.001 vs. placebo). During the sustained phase, dipyridamole-stress echocardiography was positive after both placebo and active drug (p = NS vs. placebo). Heart rate variability showed significantly higher values in power of the low frequency (LF) band and low- to high-frequency ratio (L/H), as well as significantly lower values of the power of the high-frequency (HF) band (all p < 0.001) during brief but not during sustained administration of 5-ISMN. Norepinephrine plasma levels were significantly higher (p < 0.001) during short-term 5-ISMN administration but not during the sustained phase. Our results indicate that short-term administration of 5-ISMN antagonizes dipyridamole-induced myocardial ischemia and show the loss of antiischemic efficacy in 95% of patients during sustained treatment, demonstrating that dipyridamole-stress echocardiography is a useful tool to assess the presence of nitrate tolerance. Spectral analysis of heart rate variability and norepinephrine values confirm that brief nitrate administration increases sympathetic activity, a possible crucial trigger event in the development of nitrate tolerance, whereas prolonged nitrate treatment is not associated with prolonged neurohumoral activation.

Aged↗
PubMed2003

Decrease in plasma NOx concentration by isosorbide dinitrate, an organic nitrate ester.

It has been suggested that isosorbide dinitrate (ISDN)-induced venodilation could be ascribed to preferential accumulation of the agent in venous tissues, resulting in higher concentrations of nitric oxide (NO). Here, the authors investigated whether the venodilating effect of ISDN is associated with a preferential increase in plasma concentrations of NOx (NO2- and NO3-, stable end-products of NO) in venous blood than arterial blood. Plasma NOx was measured by high-performance liquid chromatography-Griess system with a sensitivity of 0.01 microM for NO2- and 0.1 microM for NO3-. Arterial and venous blood samples were obtained after coronary angiography from the aorta and right atrium of patients with or without ischemic heart disease. Nicardipine, a calcium channel blocker, was used as a non-NO-related arteriovasodilator. At 1 mg i.v., it did not cause any changes in NOx concentration in arterial and venous blood irrespective of hemodynamic changes. However, ISDN (3 mg i.v.) increased NO2- and decreased NO3- in both arterial and venous blood, with concomitant venodilation. Further analysis revealed that plasma NO increased in the pulmonary circulation and this increase was preserved after nicardipine and ISDN, and that ISDN, but not nicardipine, increased plasma NO3- in the pulmonary circulation. The authors did not detect higher concentrations of NOx in venous blood relative to their level in arterial blood. Further studies are necessary to clarify the kinetics of NO and NO-related compounds in the whole body.

Aged↗
PubMed2003

Lack of oxidative stress during sustained therapy with isosorbide dinitrate and pentaerythrityl tetranitrate in healthy humans: a randomized, double-blind crossover study.

The mechanisms by which tolerance to organic nitrates develops are still poorly understood. Enhanced oxidative stress, i.e., increased free radical production following organic nitrate administration, has been recently suggested as a possible mechanism. A randomized, double-blind, crossover study assessed in 18 healthy young volunteers at baseline and 1 and 5 days after oral administration with therapeutically relevant doses of isosorbide dinitrate (ISDN, 30 mg TID) or pentaerythrityl tetranitrate (PETN, 80 mg TID) the effect on two index parameters of oxidative stress in vivo, i.e., urinary 8-iso-prostaglandin (PG)F2alpha and circulating 3-nitrotyrosine and their major urinary metabolites, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha and 3-nitro-4-hydroxyphenylacetic acid. In addition, urinary cGMP and serum and urinary nitrate and nitrite were determined. All parameters were quantified by gas chromatography-mass spectrometry or gas chromatography-tandem mass spectrometry except for cGMP, which was analyzed by radioimmunoassay. Serum and urinary nitrite levels increased significantly following 5-day administration of ISDN and PETN. Neither urinary excretion of 8-iso-PGF2alpha and plasma 3-nitrotyrosine nor their respective metabolites changed significantly after ISDN or PETN administration. There were no significant differences between ISDN and PETN regarding these parameters. Urinary cGMP increased significantly only after ISDN. This study is compatible with a stimulation of cGMP by ISDN, but neither ISDN nor PETN enhances systemic oxidative stress in healthy volunteers.

Adult↗
PubMedDate not supplied

BiDil (isosorbide dinitrate and hydralazine): a new fixed-dose combination of two older medications for the treatment of heart failure in black patients.

BiDil is a new fixed-dose combination of 2 older medications, isosorbide dinitrate (ISDN) and hydralazine. ISDN is an organic nitrate that is biotransformed into nitric oxide, a potent vasodilator. Hydralazine is believed to have both vasodilatory properties specific to the arteries and antioxidant properties, which address both the biochemical alterations in the failing cardiovascular system as well as the issue of nitrate tolerance. A drug regimen combining an NO stimulator (ISDN) with an antioxidant (hydralazine) favorably influences the nitroso-redox balance. Retrospective analyses of previous heart failure (HF) clinical trials comparing the combination of ISDN and hydralazine with placebo and enalapril, respectively, demonstrated a benefit in the black population, setting the precedent for a race-based therapeutic study, the African-American Heart Failure Trial (A-HeFT). A-HeFT examined the use of BiDil added to standard HF therapy in blacks with New York Heart Association functional class III and IV HF. BiDil demonstrated a 43% reduction in mortality when compared with placebo. As a result, current evidence-based treatment guidelines recommend that the addition of ISDN and hydralazine in black patients with moderate to severe HF optimized on standard therapy be considered. BiDil is currently indicated for the treatment of HF as an adjunct to standard therapy in black patients. The use of BiDil for black patients with mild disease or in nonblack patients with HF has not been studied. Future clinical trials involving an ethnically and clinically diverse population of patients would further define the role of combined ISDN and hydralazine in the treatment of HF.

Black People↗
PubMed2005

Curative isosorbide-5-mononitrate treatment, in opposition to the beneficial preventive one, aggravates the prothrombotic and proconstrictor state in cyclosporine-induced hypertensive rats.

1. The aim of the present study was to evaluate the effect of preventive and curative isosorbide-5-mononitrate (Is-5-Mn) treatment on the development of hypertension, cGMP content, thromboxane (TX) A(2)/prostaglandin (PG) I2 balance, the peripheral serotonergic system, platelet activation, lipid peroxidation and plasma lipids in cyclosporine A (CsA)-induced hypertensive rats. 2. Control, CsA (5 mg/kg per day) and Is-5-Mn (150 mg/kg per day, b.i.d.) rat groups were treated orally over a period of 7 weeks. The preventive Is-5-Mn group (Is-5-Mn + CsA) was first treated for 2 weeks with Is-5-Mn, followed by 7 weeks with both drugs; the curative Is-5-Mn group (CsA + Is-5-Mn) was treated for a period of 7 weeks with CsA and with both drugs for an additional 5 weeks. The control group received oral vehicle. 3. Whereas in the group undergoing preventive treatment the CsA-induced increase in blood pressure (BP), compared with the control group, was avoided, in the group undergoing curative treatment, the increase in BP was even higher. The decreased arterial cGMP content in the CsA group was prevented and reverted when Is-Mn was administered either preventatively or curatively with CsA. Platelet TXA2 production, although unaffected in the Is-5-Mn + CsA group, was significantly higher in the CsA + Is-5-Mn group compared with the group receiving CsA alone. Furthermore, plasma TXA2 was reduced following preventive Is-5-Mn treatment, but was worsened in the group undergoing curative therapy. Aortic PGI2 synthesis was identical in all groups. Consequently, the TXA2/PGI2 ratio was only altered in the CsA + Is-5-Mn group, demonstrating a markedly higher value. In both groups treated simultaneously with CsA and Is-5-Mn, a higher platelet 5-hydroxytryptamine (5-HT) content was obtained compared with CsA treatment alone, but only preventive treatment with Is-5-Mn resulted in a significant reduction in plasma 5-HT. Changes in ADP and collagen-induced platelet aggregation paralleled those of plasma 5-HT and TXA2: the hyperaggregation profile of the CsA group, although partially prevented, was not reverted by simultaneous treatment with Is-5-Mn and CsA. Lipid peroxidation and lipid profile values also worsened in the CsA + Is-5-Mn group compared with the group administered CsA alone. 4. In conclusion, the beneficial effects of concomitant Is-5-Mn and CsA treatment were demonstrated when Is-5-Mn was administered preventatively because not only was arterial hypertension prevented, but platelet aggregation and plasma TXA2 and 5-HT levels were also reduced. In contrast, following curative treatment, the BP, platelet/vascular vasoconstrictor balance, lipid peroxidation and plasma lipids were aggravated, recommending a judicious evaluation of the impact of nitrate therapy throughout the period of its administration.

Animals↗
PubMed1981

Treatment of acute myocardial infarction with sodium nitroprusside during 24 hours, followed by isosorbide dinitrate.

In a controlled randomized study of 328 consecutive patients admitted within 24 hours after the onset of acute myocardial infarction, 163 patients received a sodium nitroprusside infusion during 24 hours, followed by six times a day 5 mg isosorbide dinitrate for seven days and 165 patients received a glucose 5% infusion. Excluded from the study were patients with either pulmonary edema and/or cardiogenic shock, two or more previous myocardial infarctions or a systolic blood pressure of less than 95 mmHg just before entering the study. Sodium nitroprusside was titrated in such a way that systolic blood pressure was kept between 95 and 105 mmHg. Standard medical treatment for both groups was the same. CK-MB was sampled every four hours until peak value was reached. Endpoint of the study was a significant reduction in mortality within a week after starting treatment.

Clinical Trials as Topic↗
PubMed1981

The effect of pindolol and isosorbide dinitrate and their combination on exercise tolerance and ECG changes in angina pectoris.

The effect of placebo, isosorbide dinitrate (ISDN) (5 mg orally), pindolol (1.0 mg i.v.) and the combination of ISDN and pindolol was tested in 12 patients with stable, exercise-induced angina pectoris and normal resting ECG. A graded submaximal exercise test was performed on a bicycle ergometer 30 min after medication. All patients had ST depression during and shortly after exercise. ISDN and pindolol increased exercise tolerance to a similar degree but through different mechanisms. Pindolol decreased heart rate and markedly reduced ST depression in the ECG, while ISDN had no effect on ECG changes. The combination of ISDN and pindolol was superior to either drug alone in increasing exercise tolerance in angina pectoris.

Angina Pectoris↗
PubMed1988

Anti-anginal efficacy of a controlled-release formulation of isosorbide-5-mononitrate once daily in angina patients on chronic beta-blockade.

The anti-anginal effect of a controlled-release (Durules) formulation of isosorbide-5-mononitrate (5-ISMN) 60 mg, Imdur, once daily was evaluated in a randomised double-blind, placebo-controlled, crossover study with a placebo run-in period. Each period lasted for 2 weeks. A total of 70 patients (58 men and 12 women) with stable exertional angina pectoris on beta-blockade, mean age 59 years (range 39-71), were included. Exercise testing was performed on a bicycle ergometer 3 hours after the dose at the end of each period. Anginal attacks and intake of sublingual nitroglycerin tablets were noted. Imdur in combination with a beta-blocker significantly increased the total exercise capacity, the time and total work until the onset of chest pain and at 1 mm ST-depression compared with beta-blockade alone. The attack rate and the nitroglycerin consumption were significantly decreased. Headache was the only significant side-effect. In conclusion, the addition of Imdur once daily to beta-blockade significantly increased the anti-anginal effect.

Adrenergic beta-Antagonists↗
PubMed2006

Comparative study between nadolol and 5-isosorbide mononitrate vs. endoscopic band ligation plus sclerotherapy in the prevention of variceal rebleeding in cirrhotic patients: a randomized controlled trial.

BACKGROUND: After variceal bleeding, cirrhotic patients should receive secondary prophylaxis. AIM: To compare nadolol plus 5-isosorbide mononitrate (5-ISMN) with endoscopic band ligation. The end points were rebleeding, treatment failure and death. METHODS: One hundred and nine cirrhotic patients with a recent variceal bleeding were randomized: nadolol plus 5-ISMN in 57 patients and endoscopic band ligation in 52 patients. RESULTS: The mean follow-up was 17 and 19 months in nadolol plus 5-ISMN and endoscopic band ligation groups, respectively. No differences were observed between groups in upper rebleeding (47% vs. 46%), variceal rebleeding (40% vs. 36%), failure (32% vs. 22%), major complications (7% vs. 13.5%) and death (19% vs. 20%), respectively. The actuarial probability of remaining free of rebleeding, failure and deaths were similar in both groups. Time to rebleeding shows that endoscopic band ligation patients had an early rebleed, with a median of 0.5 month (95% CI: 0.0-4.2) compared with patients from nadolol plus 5-ISMN, 7.6 months (95% CI: 2.9-12.3, P < 0.013). Multivariate analysis indicated that outcome-specific predictive factor(s) for rebleeding was Child A vs. B + C (P < 0.01); for failure was Child A vs. B + C (P < 0.02); and for death ascites (P < 0.01) and rebleeding (P < 0.02). CONCLUSION: This trial suggests no superiority of endoscopic band ligation over nadolol plus 5-ISMN mononitrate for the prevention of rebleeding in cirrhotic patients.

Endoscopy, Gastrointestinal↗
PubMed1978

Plasma concentrations of isosorbide dinitrate and its metabolites after chronic high oral dosage in man.

1 We have previously reported that vasodilator headache due to isosorbide dinitrate (ISDN) can be circumvented by using small 'priming' doses for an induction period of 1-2 weeks, after which it is possible to increase to dose rapidly to 360-720 mg, daily without recurrence of headache and without toxicity. The present study corroborates this earlier finding. 2. Chronic oral administration of doses of ISDN of this order of magnitude results in prolonged high plasma concentrations of the parent compound, as well as higher levels of the metabolites 2-ISMN and 5-ISMN. 3. It is our thesis that chronic high oral dosage of ISDN saturates the intrahepatic biotransformation process, and allows high concentrations of ISDN and its metabolites to enter the systemic circulation.

Administration, Oral↗
PubMed1981

Kinetics of isosorbide dinitrate and relationships to pharmacological effects.

1 The inter-relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmacokinetics and pharmacological effects were studied in 12 angina patients following single and chronic doses of 15, 30, 60 and 120 mg. 2 Significant accumulation of intact ISDN in plasma was observed after four times a day dosing at 30, 60 and 120 mg for 1 week. 3 The area under the plasma concentration v time curve (AUC), form 0-6 h, was shown to be proportional to dose following single doses. In contrast, AUC increased disproportionately to dose after chronic dosing. 4 Pharmacokinetic correction provided modest improvements in the dose-response relationships of ISDN. 5 Adverse hypotensive effects were observed in five patients after the single 60 mg dose. These patients showed statistically higher AUC and lower intrinsic clearance of ISDN at doses of 15, 30 and 60 mg compared to those who did not develop adverse effects. A possible relationship exists, therefore, between lower drug clearance and hypersensitivity to ISDN.

Adult↗
PubMed1983

Prolonged plasma half-life after oral isosorbide dinitrate in patients with angina pectoris.

The plasma concentration of isosorbide dinitrate (ISDN) was monitored up to 24 h after a chronic oral dose of 60 mg in six patients with coronary artery disease. A terminal half-life of 7.7 +/- 2.6 h (mean +/- s.d.) was observed. The presence of this prolonged disappearance phase provided at least a partial explanation for the observed accumulation of ISDN in plasma after chronic dosing on a six hourly regimen.

Angina Pectoris↗
PubMed1984

Haemodynamics and plasma concentrations following sublingual GTN and intravenous, or inhaled, isosorbide dinitrate.

We measured plasma nitrate levels and haemodynamics following sublingual glyceryl trinitrate (GTN) (0.5 mg), or isosorbide dinitrate (ISDN) administered intravenously (0.5 mg) or by inhalation (1.25 mg) in 23 patients undergoing cardiac catheterisation for investigation of chest pain. Peak levels were detected at 90 s and 5 min following intravenous and inhaled ISDN respectively and at 3 min following sublingual GTN. Intravenous and inhaled ISDN produced similar plasma levels at 30 s and both were significantly greater than following sublingual GTN. Plasma levels were maintained for longer following inhaled ISDN than intravenous ISDN or sublingual GTN. Haemodynamic responses were qualitatively similar following each treatment; reduction in pulmonary vascular resistance and pressure and left ventricular end diastolic pressure occurred in each group. Heart rate, cardiac output and LV dP/dt.P-1 remained unchanged. Maximal haemodynamic responses were greater following ISDN than GTN, with little difference between the two preparations of ISDN. Haemodynamic responses were more sustained following inhaled ISDN than following sublingual GTN or intravenous ISDN, the latter two being similar in this respect. These findings suggest that inhaled ISDN may provide more rapid and sustained relief from angina than sublingual GTN.

Absorption↗
PubMed1986

Comparison of transdermal nitrate and isosorbide dinitrate in chronic stable angina.

The effects of transdermal nitrate (TN) (Transiderm-Nitro TTS, Geigy Pharmaceuticals, one 10 cm2 patch daily) and oral isosorbide dinitrate (ISDN) (Sorbitrate, Stuart Pharmaceuticals, 10 mg three times daily) were compared in a group of 20 patients with chronic stable angina pectoris. Treadmill exercise duration was prolonged from a median time of 365 s to 428 s after ISDN (P less than 0.05), but was unchanged after TN. The difference between the active treatments was not significant. Weekly consumption of glyceryl trinitrate (GTN) increased during treatment with TN from a median value of 5.5 to 6.3 (P less than 0.05). A decrease was observed after ISDN (7.8 to 3.9, P = NS), and the difference between the drugs was significant (P less than 0.01). Systolic arterial pressure was significantly lower during the ISDN than during the TN treatment period in both the supine (135 +/- 5 vs 128 +/- 5 mm Hg; P less than 0.05) and standing positions (134 +/- 5 vs 122 +/- 5 mm Hg; P less than 0.05). No change in weekly attack rate, the degree of ST depression at angina on treadmill testing, or the number of episodes of ST depression recorded during a 24 h period by Holter monitoring was observed after either drug. In this study, an antianginal effect was demonstrated for ISDN but not for TN. It is suggested that the dose of TN may have been inadequate to demonstrate such an effect, and further studies using a higher dose schedule will be required.

Administration, Oral↗
PubMed1989

Comparison of the immediate and long-term effects of captopril and isosorbide dinitrate as adjunctive treatment in mild heart failure.

1. The efficacy of captopril and isosorbide dinitrate (ISDN) as adjunctive therapy to digoxin and diuretics in mild heart failure was compared in a double-blind study. 2. Twenty-one patients were randomly allocated to captopril (twice or three times daily) or ISDN. Eighteen patients completed a protocol of placebo run-in, dose titration and maintenance treatment for 3 months. 3. Symptom-limited exercise tolerance, ejection fraction and radionuclide indices of diastolic function estimated by gated blood pool scan did not change with either treatment. 4. Captopril improved functional class (Canadian Cardiovascular Society) and reduced requirements for increased diuretic dosage at both 1 and 3 months of maintenance treatment. Patients treated with ISDN required increased diuretic and did not improve their functional class. Differences between the treatments were significant only for diuretic dosage requirements. 5. We conclude that adjunctive therapy of mild heart failure with captopril administered twice daily provides a diuretic-sparing effect and may improve functional class during 3 months of maintenance treatment.

Blood Pressure↗
PubMed1992

Plasma profile and haemodynamic tolerance to isosorbide-5-mononitrate in controlled-release form.

1. Plasma concentrations and some haemodynamic parameters known to be affected by nitrates, were monitored in healthy volunteers who received three different dose regimens of isosorbide-5-mononitrate (5-ISMN) over 5 day study periods. 2. No haemodynamic tolerance was found in the 60 mg once-daily dose schedule which produced high plasma concentrations during the daytime but concentrations no greater than 100 ng ml-1 at night. In contrast, a dose regimen of 60 mg followed by 30 mg 12 h later and thereafter every 8 h until the fifth day induced complete haemodynamic tolerance. With this dose regimen the minimum plasma concentrations were never below 300 ng ml-1. A significant attenuation of haemodynamic effects was also found with the third dose regimen, 60 mg followed by 30 mg 6 h later for 5 days, which produced minimum plasma concentrations of between 100 ng ml-1 to 300 ng ml-1; the degree of attenuation rose as trough plasma concentrations increased. 3. In conclusion, 60 mg 5-ISMN in a controlled-release (Durules) preparation given once daily was the only dose regimen not inducing nitrate tolerance.

Adult↗