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PubMed1984

Inhibition of platelet function by injectable isosorbide dinitrate.

The possibility that isosorbide dinitrate (ISDN) inhibits platelet function in humans has been explored in vitro and in vivo. Incubation of citrated platelet-rich plasma from healthy subjects with scalar concentrations (1.25, 12.5 and 125 micrograms/ml) of ISDN for 5 and 10 minutes resulted in a decrease in platelet aggregation after ADP, adrenaline, and arachidonic acid at the highest drug concentration (mean decrease: 72% [p less than 0.01], 56% [p less than 0.05] and 62% [p less than 0.05], respectively, with the 10-minute incubation). Also, a significant reduction (30%) in generated thromboxane (TX)B2 levels was observed after arachidonic acid (p less than 0.01). ISDN was then infused at rate of 4 mg/hour for 30 minutes in 11 patients with angina and at a rate of 30 mg/hour for 20 minutes in 8. The smaller dose, which caused minor changes in arterial pressure and heart rate, was accompanied by a marked, significant decrease in ADP- and adrenaline-induced aggregation, with a nadir at 60 minutes from the infusion stop (decreases of 40% and 51% respectively). Circulating platelet aggregates also decreased, with a minimum (-41%, p less than 0.05) at the end of the infusion. The higher infusion rate, causing marked hemodynamic effects, was not accompanied by the occurrence of clear antiplatelet effects. Thus, ISDN can affect platelet function both in vitro and in vivo. The in vivo effect occurs at lower concentrations than in vitro but is blunted when a marked hemodynamic response occurs.

Adenosine Diphosphate↗
PubMed1997

Gastric emptying of semisolid meal unaltered by 3 days' administration of a sustained-release preparation of the nitric oxide donor, isosorbide dinitrate.

BACKGROUND: Evidence has accumulated that nitric oxide is involved in the regulation of gastrointestinal motor activity. We investigated whether nitric oxide derived from a sustained-release isosorbide dinitrate (Cedocard retard) had an effect on gastric emptying and on subjective feelings. METHODS: Twelve healthy males aged 23-32 years received at weekly intervals, for 3 days twice daily, either 20 mg isosorbide dinitrate, 40 mg isosorbide dinitrate, or placebo, under random double-blind conditions. After a further dose on day 4, subjects ate a 1168 kJ semisolid meal, the emptying of which was recorded scintigraphically for 50 min. RESULTS: Neither dosage of isosorbide dinitrate had an effect on emptying which differed from the effect of placebo and the effects of the two dosages were the same. The radioactivity remaining in the stomach 50 min postprandially was 68.5% +/- 4.5 S.E.M. after placebo, 65.4 +/- 5.6% after 20 mg isosorbide dinitrate and 66.1 +/- 4.4% after 40 mg isosorbide dinitrate. With 40 mg isosorbide dinitrate, all 12 subjects complained of persistent headache, whereas only slight headache was reported by 7 subjects on 20 mg isosorbide dinitrate and by 1 subject on placebo. CONCLUSION: Twenty and 40 mg doses of sustained-release isosorbide dinitrate twice daily had no effect on the gastric emptying of a semisolid meal, but dose-dependently induced headaches.

Adult↗
PubMed1990

Nifedipine and isosorbide dinitrate alone and in combination for patients with chronic stable angina: a double-blind crossover study.

Since not all patients tolerate beta-blockers, the efficacy of nifedipine and isosorbide dinitrate was evaluated alone and in combination in patients with stable angina pectoris. The study was a randomized double-blind crossover design with patients titrated to maximally tolerated doses of both drugs. Phases included isosorbide dinitrate alone, nifedipine alone, and isosorbide dinitrate plus nifedipine in combination, with efficacy determined by stress testing. Eleven men and one woman patient with a mean age of 60 years and a mean of five anginal episodes/week completed the study. Patients were in New York Heart Association (NYHA) classes I, II, and III. With nifedipine alone compared with isosorbide dinitrate alone, patients had fewer angina attacks/week (p less than 0.02), exercised longer before experiencing angina (p less than 0.03), and had less ST segment depression during (p less than 0.03) or after (p less than 0.05) exercise. When patients received isosorbide dinitrate plus nifedipine, only time to onset of angina during exercise (p less than 0.05) was significantly different from the response with isosorbide dinitrate alone. Analysis of variance between nifedipine and isosorbide dinitrate plus nifedipine was not significant. Diastolic blood pressure with isosorbide dinitrate plus nifedipine (p less than 0.04) was lower than with isosorbide dinitrate alone. No significant differences in systolic blood pressure were noted between the treatment groups. The drugs alone and in combination were relatively well tolerated. Nifedipine alone may be superior to isosorbide dinitrate alone. The combination of isosorbide dinitrate plus nifedipine demonstrated no advantage over nifedipine alone compared with isosorbide dinitrate alone.

Angina Pectoris↗
PubMed1988

Effects of isosorbide dinitrate and diltiazem on Ca2+ flux and contraction in artery.

We studied the effects of isosorbide dinitrate and diltiazem on histamine-stimulated 45Ca fluxes and contractions of isolated porcine coronary artery. Isosorbide dinitrate was slightly more potent as an inhibitor of intracellular compared to extracellular calcium-dependent contraction. Isosorbide dinitrate inhibited histamine-stimulated calcium efflux and intracellular calcium-dependent contraction over similar concentration ranges. Isosorbide dinitrate partially inhibited histamine-stimulated calcium influx, but this effect was significant only at high concentration and correlated weakly with inhibition of contraction that was dependent on extracellular calcium. Diltiazem more potently inhibited extracellular vs. intracellular calcium-dependent contraction. Diltiazem partially inhibited histamine-stimulated calcium efflux and intracellular calcium-dependent contraction to similar extents (55-60%) and produced similar concentration-response relationships for inhibition of histamine-stimulated calcium influx and extracellular calcium-dependent contraction. The data suggest that alterations of cellular calcium metabolism are major mechanisms of vascular smooth muscle relaxation by isosorbide dinitrate and diltiazem, but that the specific alterations differ for the two drugs. Isosorbide dinitrate may inhibit contraction primarily by enhancing intracellular calcium sequestration, but possibly also by inhibiting agonist-stimulated calcium influx at high isosorbide dinitrate concentrations. Diltiazem primarily inhibits stimulated calcium influx, but may also inhibit intracellular calcium release.

Animals↗
PubMed1979

Simultaneous determination of isosorbide dinitrate and its mononitrates in human plasma by capillary column GLC.

A previously described electron-capture GLC method for determination of isosorbide dinitrate in human plasma was adapted for the simultaneous determination of isosorbide dinitrate, isosorbide 2-mononitrate, and isosorbide 5-mononitrate using a capillary column. Quantitation was done with two internal standards. The lower limits of detection were approximately 0.5 ng/ml of plasma for isosorbide dinitrate, 2 ng/ml for isosorbide 2-mononitrate, and 20 ng/ml for isosorbide 5-mononitrate.

Biotransformation↗
PubMed1981

Fate of isosorbide dinitrate and mononitrates in patients with renal failure.

Isosorbide dinitrate 10 mg, isosorbide 5-mononitrate 5 mg and isosorbide 2-mononitrate 5 mg were administered orally to subjects with and without renal failure, and the plasma concentrations of isosorbide dinitrate and of both the mononitrates were measured. There was no striking difference in plasma concentration as a function of time between subjects with and without renal failure, except for a somewhat higher isosorbide 5-mononitrate concentration after administration of this metabolite to uraemic patients.

Adult↗
PubMed1977

Quantitative determination of isosorbide dinitrate and two metabolites in plasma.

A GLC method for the determination of plasma isosorbide dinitrate and two metabolites, isosorbide 2-mononitrate and isosorbide 5-mononitrate, is described. The three substances are extracted from alkalinized plasma with ether. Quantitation is effected by electron-capture detection after GLC separation with a 30% SE-30 column. The unusually heavy liquid phase loading is necessary to eliminate irreversible adsorption on the solid support. The electron-capture detector provides excellent sensitivity and specificity because of the electronegative nature of the nitric ester. The method was used to study the blood levels of isosorbide dinitrate and two metabolites in four beagle dogs after single oral doses of 40 mg of isosorbide dinitrate and in two human volunteers after a sublingual dose of 10 mg of isosorbide dinitrate.

Administration, Oral↗
PubMed1983

Fate of orally given isosorbide dinitrate in man: factors of variability.

After oral administration of isosorbide dinitrate, plasma concentrations of isosorbide dinitrate and mononitrates can be measured. An attempt was made to identify a number of factors which influence these plasma concentrations. Presence of renal failure, acute or chronic treatment with beta-blocking agents, and chronic cimetidine treatment did not influence the plasma concentrations. In a number of patients with cirrhosis, however, plasma concentrations of isosorbide dinitrate were found to be higher than in noncirrhotic patients.

Administration, Oral↗
PubMed1998

Withdrawal effects of antianginal therapy: comparison of isosorbide dinitrate and nifedipine.

We compared the effects of abrupt cessation of nifedipine and isosorbide dinitrate therapy in patients with stable angina pectoris. Eighteen males were studied. Each patient received isosorbide dinitrate and nifedipine continuously for 5 weeks by randomised cross-over technique. Exercise treadmill tests were performed before each treatment period, at the beginning of treatment, 4 weeks after initiation of treatment and on the first and eighth days of drug withdrawal. At the end of treatment the antianginal effect of both agents attenuated (versus acute administration). Abrupt cessation of isosorbide dinitrate caused only a tendency towards decrease in exercise tolerance versus pre-treatment level. Alternatively, abrupt cessation of nifedipine resulted in substantial deterioration in exercise tolerance, which was statistically significant 21 and 24 h after the last dose administration. The number of anginal attacks increased >25% in two patients after cessation of isosorbide dinitrate and in eight patients after cessation of nifedipine. In no patient rest angina episodes appeared after stopping of isosorbide dinitrate, however, after stopping of nifedipine rest angina episodes appeared in three patients. We conclude that withdrawal phenomenon of nifedipine is much more pronounced than that of isosorbide dinitrate and may emerge on the first day of drug cessation. Such a phenomenon may be evident even in patients in whom nifedipine effect have attenuated due to the development of tolerance.

Adult↗
PubMed1998

Vascular hyporeactivity persists despite increased contractility after long-term administration of isosorbide dinitrate in portal hypertensive rats.

BACKGROUND/AIMS: Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamics. Isosorbide dinitrate is an effective portal hypotensive drug. The present study aimed to investigate whether chronic administration of isosorbide dinitrate could affect vascular responsiveness in portal hypertensive rats. METHODS: Portal hypertension was induced by partial portal vein ligation. Sham-operated (Sham) rats served as controls. There were four animal groups for this study: portal vein ligation-isosorbide dinitrate group, portal vein ligation-vehicle (Veh) group, Sham-isosorbide dinitrate group and Sham-Veh group. Isosorbide dinitrate (5 mg x kg(-1) x 12 h(-1) was given by gavage for 8 days starting 1 day before ligation and continuing thereafter. Mesenteric arteries were removed for contractile study after hemodynamic measurement. RESULTS: Contractile responses to KCI (15-90 mM) and phenylephrine (10(-9)-10(-4) M) were recorded. Both vascular reactivity and sensitivity were significantly reduced in portal vein ligation rats as compared to Sham rats. Chronic isosorbide dinitrate treatment reduced portal venous pressure in portal vein ligation rats. Moreover, the maximal contractile responses to KCl and phenylephrine were significantly enhanced in both portal vein ligation and Sham rats after isosorbide dinitrate treatment, but relative hyporeactivity persisted in portal vein ligation rats. In contrast, a single dose of isosorbide dinitrate did not alter the contractile sensitivity or reactivity to KCl or phenylephrine in either portal vein ligation or Sham rats. CONCLUSION: Our results show that long-term administration of isosorbide dinitrate enhanced vascular contractility in both portal vein ligation and Sham rats, but relative hyporeactivity persisted in portal vein ligation rats.

Administration, Oral↗
PubMed1980

Haemodynamic effects of oral salbutamol alone and in combination with sublingual isosorbide dinitrate in patients with severe congestive cardiac failure.

To examine possible augmentation of the effects of isosorbide dinitrate by salbutamol, haemodynamic measurements were made in 10 patients with severe chronic congestive cardiac failure who received isosorbide dinitrate 2.5 to 25 mg sublingually and salbutamol 4 to 12 mg orally, alone and in combination. Isosorbide dinitrate reduced mean left ventricular filling pressure from 29 to 18 mmHg and increased mean cardiac index from 1.7 to 2.0 1/min per m2, with no significant change in mean heart rate. Systemic arterial mean pressure fell from 85 to 72 mmHg. Salbutamol increased cardiac index from 1.8 to 2.2 1/min per m2. There was no significant change in left ventricular filling pressure, heart rate, or systemic arterial pressure. Compared with control, combined isosorbide dinitrate and salbutamol reduced left ventricular filling pressure from 27 to 19 mmHg and increased cardiac index from 1.8 to 2.7 1/min per m2, with no significant change in heart rate. Systemic arterial pressure fell from 82 to 75 mmHg. The reduction in left ventricular filling pressure by combined treatment was similar to that produced by isosorbide dinitrate alone, but the increase in cardiac index was significantly greater than that produced either by isosorbide dinitrate alone or salbutamol alone. Combined sublingual isosorbide dinitrate and oral salbutamol have an additive effect in improving left ventricular performance in patients with severe chronic congestive cardiac failure.

Aged↗
PubMed1984

Hemodynamic effects of high-dose sustained-action oral isosorbide dinitrate in stable angina.

Hemodynamic effects of sustained-action oral isosorbide dinitrate (40 or 80 mg) were studied in 10 patients with stable angina for a period of 16 hours. Control hemodynamic parameters monitored for eight hours prior to the administration of isosorbide dinitrate showed no significant change. However significant reduction in mean arterial pressure, cardiac index, pulmonary artery wedge pressure, mean pulmonary artery pressure, double product (systolic pressure multiplied by heart rate), stroke volume index, and stroke work index occurred in the first two hours and persisted for 12 hours following the administration of isosorbide dinitrate. Heart rate did not change significantly for 12 hours. It can be concluded that the hemodynamic effects of sustained-action oral isosorbide dinitrate occur in the first two hours and last up to 12 hours. The predominant hemodynamic effect appears to be on the myocardial preload. The antianginal effect of the drug could be attributed to the reduction of myocardial oxygen demand reflected by a decrease in the double product and stroke work. The duration of the hemodynamic changes observed in this study indicates that high-dose oral isosorbide dinitrate could be administered conveniently two or three times daily.

Administration, Oral↗
PubMed1998

Effect of long-term octreotide and isosorbide dinitrate on haemodynamics in rats with portal vein stenosis.

1. Both octreotide and isosorbide dinitrate have been shown to have portal hypotensive effects in animals with portal hypertension. Moreover, in both animals and humans with portal hypertension, the reduction of portal pressure was enhanced when nitrovasodilators were combined with propranolol or vasopressin. The present study was undertaken to evaluate the effect of long-term administration of octreotide and isosorbide dinitrate on haemodynamics in rats with portal vein stenosis. 2. Portal hypertension was induced by portal vein stenosis. Portal hypertensive rats were allocated into one of four groups (eight rats in each group): vehicle group, octreotide group (100 micrograms/kg via subcutaneous injection every 12 h), isosorbide dinitrate group (5 mg/kg via gastric gavage every 12 h) and combined treatment group. Drug was given for eight consecutive days, starting 1 day before surgery. Haemodynamic values were measured using a radioactive microsphere technique. 3. Long-term octreotide treatment decreased portal pressure and improved the hyperdynamic circulation. In contrast, long-term administration of isosorbide dinitrate reduced portal pressure but did not ameliorate vasodilatation. A combination of octreotide and isosorbide dinitrate improved the hyperdynamic circulation with a reduction of portal pressure. In addition, the mean value of portal pressure after combination treatment was significantly lower than in rats receiving octreotide alone. 4. These results showed that, in rats with portal hypertension, long-term combined administration of octreotide and isosorbide dinitrate improved the hyperdynamic circulation together with a more profound reduction of portal pressure than rats receiving octreotide alone.

Animals↗
PubMed1996

A comparison of nifedipine once daily (Adalat LA), isosorbide mononitrate once daily, and isosorbide dinitrate twice daily in patients with chronic stable angina.

The efficacy of nifedipine gastrointestinal therapeutic system (GITS), 60-90 mg o.d., isosorbide dinitrate, 40-60 mg b.d., and isosorbide mononitrate slow-release, 50-100 mg o.d. was assessed in a six week double-blind, parallel-group study in patients with stable angina on chronic beta-blocker treatment. Of 339 patients who entered the study, 229 were eligible for the valid case analysis of efficacy and 335 for the safety analysis. Nifedipine GITS was significantly better than isosorbide dinitrate (P < or = 0.025) in prolonging time to 1 mm ST-segment depression, time to maximum ST-segment depression, time to occurrence of angina and total exercise duration, in addition to reducing the number of angina attacks and glyceryl trinitrate consumption after six weeks therapy. Nifedipine GITS was also significantly better than isosorbide mononitrate (P < or = 0.025) in prolonging time to occurrence of angina and time to 1 mm ST-segment depression after six weeks therapy. The incidence of headache was considerably higher in both the isosorbide dinitrate and isosorbide mononitrate groups (40% and 41%, respectively) than in the nifedipine GITS group (9.5%, P < or = 0.001), and was the main reason for withdrawal from the study (isosorbide dinitrate 18/99, isosorbide mononitrate 17/99, nifedipine GITS 2/95). Peripheral oedema was more common in patients treated with nifedipine GITS (12.5%) compared to nitrates (2% in both groups, P < or = 0.01), but resulted in withdrawal of only one patient (treated with nifedipine GITS). This study suggests that the efficacy and tolerability of nifedipine GITS is superior to long acting nitrates as second-line therapy to beta-blockade in the treatment of chronic stable angina.

Adult↗
PubMed1982

Isosorbide dinitrate and nifedipine treatment of achalasia: a clinical, manometric and radionuclide evaluation.

The effects of sublingual isosorbide dinitrate (5 mg) and nifedipine (20 mg) were compared in 15 patients with achalasia. The parameters examined included the manometric measurement of the lower esophageal sphincter pressure, the radionuclide assessment of esophageal emptying and the clinical response. The mean basal lower esophageal sphincter pressure fell significantly after both drugs (p less than 0.01), with a maximum fall of 63.5% 10 min after receiving isosorbide dinitrate, but by only 46.7% 30 min after nifedipine. The esophageal radionuclide test meal retention was significantly less (p less than 0.01) only after receiving isosorbide dinitrate. The drug improved initial esophageal emptying by its effect on the lower esophageal sphincter and by relieving the test meal hold-up noted to occur at the junction of the upper and midesophagus. Eight patients cleared their test meal within 10 min after isosorbide dinitrate administration while only two did so after nifedipine. Subjectively, 13 patients had their dysphagia relieved by isosorbide dinitrate and 8 by nifedipine. However, this relief was not confirmed in 4 patients by the radionuclide study and they, as well as the other 3 patients who did not respond to therapy, were referred to pneumatic dilatation. Side effects were more prominent after nitrates. Three of the patients are currently receiving nifedipine and 5 patients received isosorbide dinitrate therapy for 8-14 mo. The radionuclide test meal is currently the best way of objectively evaluating drug therapy in patients with achalasia. Isosorbide dinitrate is more effective than nifedipine in relieving their symptoms.

Adolescent↗
PubMed1976

Hemodynamic effects of isosorbide dinitrate vs nitroglycerin in patients with unstable angina.

The hemodynamic response to nitroglycerin administration, to sublingual or oral administration of isosorbide dinitrate, or to a placebo was evaluated and compared in 37 patients with unstable angina pectoris under resting, pain-free conditions. Patients with congestive heart failure were not included in this study. Serial measurements of mean arterial blood pressure (MAP), pulmonary arterial end-diastolic pressure (PAEDP), cardiac index (CI), and heart rate (HR) were obtained for one hour following nitroglycerin administration and for four hours following sublingual or oral administration of isosorbide dinitrate. Echocardiographic end-diastolic volume (EDV) measurements were obtained for the groups receiving isosorbide dinitrate or placebo. There was a significant (P less than 0.05 or less than 0.1) reduction of the MAP (5 to 10 mm Hg) that persisted for more than four hours following both sublingual and oral administration of isosorbide dinitrate. The changes in the PAEDP, HR, and CI following sublingual or oral administration of isosorbide dinitrate were small and not significant. In the group receiving isosorbide dinitrate sublingually, the EDV was reduced by more than 30 ml below the placebo group (P less than 0.1) for up to four hours. The effects of nitroglycerin administration were similar in magnitude but of much shorter duration (three to four hours for sublingual and oral administration of isosorbide dinitrate vs 15 to 30 minutes for nitroglycerin). These data demonstrate that the duration of the hemodynamic effects of sublingually and orally administered isosorbide dinitrate in patients with unstable angina pectoris and normal resting hemodynamics is 8 to 12 times longer than that of nitroglycerin.

Administration, Oral↗
PubMed1997

Effects of 3-days' intake of a sustained-release preparation of the nitric oxide donor, isosorbide dinitrate, on oesophageal motility.

BACKGROUND: Nitric oxide plays an important role in gastrointestinal motility. We evaluated the effects of a sustained-release preparation of the nitric oxide donor isosorbide dinitrate on swallow-initiated oesophageal contractions and the lower oesophageal sphincter. METHODS: Twelve healthy men, aged 23-32 years, received, at 1-week intervals and under random double-blind conditions, for 3 days either 20 mg isosorbide dinitrate, 40 mg isosorbide dinitrate or placebo twice daily (b.d.). One hour after a further dose on day 4, oesophageal motility was recorded for 30 min using a multilumen catheter with a Dent sleeve straddling the lower oesophageal sphincter and side-hole openings 0, 3, 6 and 9 cm proximal to the sleeve. Contractile responses to twelve 5-mL water swallows were evaluated. RESULTS: Amplitude, duration, propagation velocity and onset latency of oesophageal contractions were not affected by either dosage of isosorbide dinitrate. Lower oesophageal sphincter resting pressure was significantly lower after 40 mg (15.1 mmHg +/- 1.2 S.E.M.) and 20 mg isosorbide dinitrate b.d. (15.0 +/- 1.0 mmHg) than after placebo (17.9 +/- 1.7 mmHg; P < 0.025). Headache was reported by all subjects on 40 mg isosorbide dinitrate, seven subjects on 20 mg and by one on placebo. CONCLUSIONS: Twenty and 40 mg sustained-release isosorbide dinitrate twice daily had no effect on swallow-initiated oesophageal contractions but decreased lower oesophageal sphincter resting pressure.

Adult↗
PubMed1977

Electron-capture GLC determination of nanogram to picogram amounts of isosorbide dinitrate.

A GLC method for the determination of plasma isosorbide dinitrate using electron-capture detection is described. The organic nitrates are especially suited for electron-capture detection if the detector temperature is optimized for maximum sensitivity, e.g., 175 degrees. Proper maintenance of the detector and column assures reproducible data in the low nanogram range. The extraction procedure described is simple, efficient, and expedient for processing large numbers of samples. The method was used to study plasma levels in four human volunteers after a single dose of a 5-mg chewable isosorbide dinitrate tablet. Concentration levels of isosorbide dinitrate as low as 0.5 ng/ml of plasma can be measured by this procedure.

Adult↗