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At least 19 recordsLinked to original sources
PubMed1990

Concentrations of isosorbide dinitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate in human vascular and muscle tissue under steady-state conditions.

The concentrations of isosorbide dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN) were determined in plasma (PL), saphenous vein wall (SV) and pectoral muscle (PM) from 8 patients undergoing coronary bypass surgery. The patients were pretreated for 2 days with ISDN 240 mg per day (standard release formulation) in 4 doses of 40 mg and one dose of 80 mg. The plasma and tissue samples were obtained during the operation, 10-12 h after the last dose. Isosorbide-2-mononitrate and isosorbide-5-mononitrate were present in plasma and tissues in the same concentration ranges with molar concentration ratios of 0.88 (IS-2-MN: PM/PL), 0.85 (IS-5-MN: PM/PL), 0.99 (IS-2-MN: SV/PL) and 1.06 (IS-5-MN: SV/PL). Mean ISDN concentrations in tissue were considerably higher than in plasma; the molar concentration ratios were 4.9 (SM/PL) and 7.21 (SV/PL). The accumulation of ISDN in vessel walls may contribute to its greater vascular action compared to the mononitrates, but it may also facilitate the development of tolerance during long-term treatment.

Aged↗
PubMed1989

Pharmacokinetics of isosorbide dinitrate, isosorbide-2-nitrate and isosorbide-5-nitrate in renal insufficiency after repeated oral dosage.

The pharmacokinetics of isosorbide dinitrate (ISDN) and its two active metabolites isosorbide-2-nitrate (IS-2-N) and isosorbide-5-nitrate (IS-5-N) were studied in 20 patients with normal and impaired renal function after repeated oral doses of standard 20 mg tablets ISDN t.i.d. Blood samples were taken in the steady-state on days 2 and 14, and the plasma concentrations were measured by electron capture capillary gas chromatography. We found a wide variation of pharmacokinetic parameters (AUCss0-8 and t1/2) of ISDN, IS-2-N, and IS-5-N in our patients. No correlation was detected between AUCss0-8 or t1/2 and the degree of renal insufficiency. No drug accumulation was observed after 14 days of administration.

Administration, Oral↗
PubMed1976

Polarographic determination of isosorbide dinitrate.

Isosorbide dinitrate and two isomeric isosorbide mononitrates are shown to be polarographically reducible in aqueous sodium perchlorate or potassium chloride solution. The current, measured at -1.6 v, versus the saturated calomel electrode is proportional to the concentration of organic nitrate in the 10-100-mug/ml range. Inorganic nitrate produces no interference. However, the mononitrate isomers produce an additive response to isosorbide dinitrate and cannot be determined individually. The polarographic method is applicable to single-tablet assay for content uniformity determination, with precision and accuracy comparable to automated colorimetric analysis. Comparison is made between replicate analyses obtained polarographically and by IR and automated colorimetric analysis for six different commercially available formulations. The polarographic determination is sensitive, specific for nitrate esters, precise, requires little sample preparation, and utilizes relatively inexpensive apparatus.

Autoanalysis↗
PubMed1990

Nitrates: why and how should they be used today? Current status of the clinical usefulness of nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate.

Nitrates are highly effective both in terminating acute attacks of angina pectoris and in the prophylaxis of symptomatic and asymptomatic myocardial ischemia. Preload reduction by venodilatation is the prevailing mechanism of nitrates in patients with chronic stable angina and is the unique feature distinguishing them from beta and calcium-channel blockers. Nitrates dilate coronary arteries not only in pre- and poststenotic vessels, but also in eccentric lesions. In patients with endothelial dysfunction, nitrates seem to be the physiological substitute for endothelium-derived relaxing factor. During the past decade, however, there has been substantial evidence of a clinically relevant loss of the anti-ischemic effects ("nitrate tolerance"). Many studies with oral dosing of isosorbide dinitrate or isosorbide-5-mononitrate at least three times daily have proven nitrate tolerance in patients with coronary artery disease and/or congestive heart failure. Complete loss of anti-ischemic effects after repetitive, continuous patch attachments has also been found. As we first showed in 1983, intermittent therapy with once-daily ingestion of high-dose sustained-release isosorbide dinitrate was successful in preventing the development of tolerance. Similarly, tolerance to isosorbide-5-mononitrate also does not develop when it is ingested once daily. It is now generally accepted that a daily low-nitrate interval is required to prevent tolerance development. Although the minimal patch-free interval required to prevent tolerance needs further investigation, a 12-h patch-free interval should prevent tolerance in most patients. The prolonged duration of action of once-daily high-dosage administration of sustained-release formulations, the improved patient compliance with a single daily administration, and the increased likelihood of maximal anti-ischemic effects are important reasons for recommending high single daily doses of isosorbide dinitrate or isosorbide-5-mononitrate.

Angina Pectoris↗
PubMed1986

Nitro compounds (isosorbide dinitrate, 5-isosorbide mononitrate and glyceryl trinitrate) on the femoral vein and femoral artery.

In organ bath studies, the selectivity of isolated femoral vein and artery of rabbit to isosorbide dinitrate (ISDN), 5-isosorbide mononitrate (ISMN), major metabolite of ISDN, and glyceryl trinitrate (GTN) was compared. The femoral vein and artery contracted by norepinephrine were relaxed by all the nitro compounds dose-dependently. Potency order was GTN greater than ISDN greater than ISMN. The maximum inhibitory responses to the nitrocompounds and their pIC50 values (negative logarithms of doses to induce the 50% response) were greater in the femoral vein than in the femoral artery. For ISMN a 3 times greater sensitivity of femoral vein than of femoral artery was found.

Animals↗
PubMed1987

Effects of nitro compounds, isosorbide dinitrate, 5-isosorbide mononitrate and glyceryl trinitrate on Ca-uptake into Ca-stores and Ca-release from Ca-stores in rabbit isolated femoral veins and femoral arteries.

In organ bath studies, effects of isosorbide dinitrate (ISDN), 5-isosorbide mononitrate (ISMN), a major metabolite of ISDN, and glyceryl trinitrate (GTN) on Ca-uptake into Ca-stores and Ca-release from Ca-stores were tested in the rabbit isolated femoral veins and femoral arteries. ISDN (10(-4) M) and GTN (10(-4) M) inhibited Ca-uptake in the femoral veins but not in the femoral arteries. The selectivity to the femoral veins was not observed in ISMN (10(-3) M) and GTN (3 X 10(-6) M). All the nitro compounds inhibited Ca-release from Ca-stores more effectively in the femoral veins than in the femoral arteries. The present results may explain the selectivity of the nitro compounds to the femoral veins.

Animals↗
PubMed1989

Effect of pertussis toxin and the cGMP lowering agent LY83583 on the relaxation induced by nitrates in isolated bovine mesenteric artery. A comparison between glyceryl trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate.

The effect of pertussis toxin (PTX) and the cyclic GMP-lowering agent LY83583 on the relaxatory response induced by glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN) in bovine mesenteric artery was investigated. Pretreatment with PTX (100 ng/ml; 2h) induced a 100-fold right shift of the concentration-effect curve for GTN, while no effect on the relaxatory response elicited by ISDN and ISMN was seen 10 microM LY83583 markedly reduced the relaxatory effect of all the organic nitroesters. Based on the different sensitivity towards PTX it is suggested that GTN induces vascular smooth muscle relaxation by a partly different mechanism than ISDN and ISMN. However, cGMP seems to play a crucial role in mediating the relaxatory response of all the tested organic nitroesters since LY83583 profoundly suppressed the relaxatory response.

Aminoquinolines↗
PubMed1985

The effect of isosorbide dinitrate and isosorbide-5-mononitrate on prostacyclin (PGI2) and thromboxane A2 (TXA2) generation in rat and human arteries.

The mechanism by which nitrates produce relaxation of the vascular smooth muscle and anti-aggregatory effect on platelets has not been understood. Several reports have suggested that vasoactive prostaglandin generation may account for part of the pharmacological action of nitroglycerin. However, few studies have been reported that isosorbide dinitrate or its main metabolite, isosorbide-5-mononitrate, directly stimulates prostacyclin (PGI2) generation in blood vessels. We examined the effect of ISDN and 5-ISMN on PGI2 and thromboxane A2 (TXA2) generation in rat thoracic aorta and human thoracic aorta and coronary artery. The stimulation of PGI2 generation was dependent on the concentration of ISDN and the maximum PGI2 generation was effected by ISDN 5.0 ng/ml in both rat and human vessels. The ratio of peak to basal PGI2 generation was about 1.6 with rat thoracic aorta and about 1.6 with human thoracic aorta and about 1.3 with human coronary artery. On the other hand, TXA2 generation showed a smaller increase than that of PGI2 with ISDN used in the therapeutic dose range and 5-ISMN did not significantly affect PGI2 or TXA2 generation. Previous studies of the effect of cyclooxygenase inhibitor, for example indomethacin, on the vasodilating response to nitrates have given conflicting results. It is believed, however, that ISDN is partially, not wholly, associated with the hemodynamic and platelet antiaggregation effects due to vascular PGI2 generation, which may play a beneficial role in inhibiting coronary vasospasm during anginal attacks.

Aged↗
PubMed1991

[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.

Adult↗
PubMed1985

[Bioavailability of isosorbide dinitrate and isosorbide-5-mononitrate under steady-state conditions].

The relative bioavailability of isosorbide dinitrate (ISDN) and its mononitrate metabolites (IS-2-MN, IS-5-MN) was determined under repetitive dose conditions in 8 healthy volunteers using a randomised, crossover design. Reference drugs were non-sustained release ISDN (Isoket 20) and IS-5-MN (Ismo 20). The relative bioavailability of ISDN after Iso Mack Retard was 69%, for two development products 78% and 79%, and 87% for Isoket Retard. The bioavailability of IS-2-MN and IS-5-MN in sustained release preparations was 6-16% and 1-17% lower, respectively. Whereas the sum total for the area under the concentration-time curve (ISDN and metabolites) for Iso Mack Retard 20 mg was also significantly lower, there was no significant difference in this parameter between Isoket retard 20 and Isoket 20. Taking IS-5-MN non-retard as reference, the bioavailability of IS-5-MN and total nitrate in all ISDN preparations examined was significantly lower.

Adult↗
PubMedDate not supplied

Nitrate tolerance: hemodynamic effects of intravenous isosorbide dinitrate after sustained oral isosorbide dinitrate administration.

To determine whether hemodynamic effects of isosorbide dinitrate (ISDN) diminish and disappear during sustained administration, nine patients with recent myocardial infarction received 10 mg of ISDN intravenously before and 1, 4, 12, 24, and 48 weeks after sustained oral administration of 20 mg of the slow-release form of ISDN four times daily. Blood pressure always decreased after intravenous ISDN; the decrease tended to be diminished when preceded by oral ISDN, but no further attenuation in blood pressure was noted. The decrease in blood pressure was associated with consistent and nonsignificant increases in heart rate after intravenous ISDN. Plasma ISDN levels were not affected by prior oral ISDN. Plasma isosorbide 2-mononitrate and isosorbide 5-mononitrate levels were consistently higher when preceded by oral ISDN. The results suggest that the hemodynamic and metabolic properties of ISDN are preserved even after sustained therapy.

Administration, Oral↗
PubMed1986

Equal anti-ischemic properties of isosorbide dinitrate plus verapamil and isosorbide dinitrate plus propranolol. A randomized, double-blind and crossover study.

Although nitrates are the basic treatment for patients with ischemic heart disease and numerous clinical studies have compared the anti-ischemic effects of different combinations with beta-blockers and/or calcium antagonists, no study is known on a controlled intraindividual comparison of the combination nitrate plus beta-blocker with the combination nitrate plus a heart rate-decreasing calcium-antagonist. Therefore we performed a randomized, double-blind and crossover study to compare the effects of 80 mg isosorbide dinitrate in slow-release form (ISDN, once-daily) plus 120 mg verapamil (t.i.d.) with those of 80 mg ISDN plus 80 mg propranolol (b.i.d.). After these two phases of 3 weeks' duration respectively, patients received the combination of all three drugs with the same dosages in a single-blind manner. In addition to the standard inclusion criteria, a pathological exercise-ECG even after ISDN was required as well as a left ventricular ejection fraction (EF) of greater than or equal to 35%. This protocol could be completed in 26 of the 30 enrolled patients. The combination ISDN plus verapamil proved to exert the same anti-ischemic effects as the combination ISDN plus propranolol. The triple therapy showed a further improvement of exercise induced ischemia without deterioration of the EF at rest or during exercise. Even though only this triple therapy led to an optimal anti-ischemic result in about one third of the patients, it should be initiated cautiously, since symptomatic bradycardia may occur.

Blood Pressure↗
PubMed1989

Pharmacokinetics of isosorbide dinitrate and isosorbide-5-mononitrate.

Short-acting nitrates like glyceryl trinitrate are most suitable for interrupting attacks of angina pectoris, long-acting nitrates for their prophylaxis. A salient feature of drugs used in prophylaxis is a long duration of action. Among many organic nitrates developed for this purpose, ISDN became the most prominent. ISDN is metabolized to isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) which are pharmacologically active. Since denitration is practically the only way of elimination, the denitration rate of the compounds is proportional to their total body clearance, which is 3.2 l/min for ISDN, 0.371 l/min for IS-2-MN and 0.124 l/min for IS-5-MN. Their terminal elimination half-life is 63, 108 and 264 min respectively. These figures are the weighted means from studies with intravenous administration. Several authors determined the AUCs of ISDN and its mononitrates after administration of ISDN. From the AUCs and the respective total body clearances, the amounts of ISDN were calculated which enter the systemic circulation intact, and those of the mononitrates formed by denitration of ISDN. After intravenous administration of ISDN, 62% were metabolized to IS-5-MN, 24% to IS-2-MN. The remaining 14% must be eliminated by other routes. After oral administration as plain tablets, 26% of the ISDN enter the systemic circulation intact. Forty-seven percent of the dose are metabolized to IS-5-MN during absorption, 17% after absorption. The figures for IS-2-MN are 14% and 5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1985

History of the synthesis and pharmacology of isosorbide dinitrate.

A major research program in the University of Maryland School of Medicine, Department of Pharmacology, in the 1930s was the preparation of a large number of sugar alcohols and their anhydrides as substitute carbohydrates for diabetic diets. As an outgrowth of this work, many of these polyols were converted to their nitrate esters and investigated for their vasodilating properties. The organic nitrates that were synthesized were examined for their potency, duration of action, and possible therapeutic use. It was demonstrated that, contrary to prior belief, the depressor and vasodilating action was exhibited by their own molecular structure and not through hydrolysis and reduction to nitrite. The search for the finer mechanism(s) of action on the vascular musculature showed that these nitrated polyols and their anhydrides inhibited arterial adenosine triphosphatase, although this enzyme inhibition did not correlate with pharmacologic activity. Today the mechanism of action of these drugs is not clearly understood at the cellular level. The 1,4:3,6-dianhydrosorbitol 2,5-dinitrate (isosorbide dinitrate) was synthesized, studied, and reported in 1940. It appeared to be a useful drug because blood levels of the unhydrolyzed ester were found to persist for long periods of time. Subsequent clinical studies in the 1960s demonstrated its prophylactic value in angina pectoris and its prolonged action as a therapeutic asset. In 1967 the mononitrate was shown to be formed in vivo when the dinitrate was administered orally and has been studied as the possible pharmacodynamically active moiety.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMedDate not supplied

Assessment of antianginal efficacy of long-acting sustained release isosorbide dinitrate in comparison with short-acting isosorbide dinitrate.

A quadruple blind randomized cross-over study evaluated the therapeutic efficacy of twice a day long acting sustained release isosorbide dinitrate (SRISDN) in comparison with 4 times daily of the short acting isosorbide dinitrate in 18 patients with stable angina pectoris (NYHA class II-III) with a positive exercise treadmill test. The antianginal effect of sustained release isosorbide dinitrate (SRISDN) (exercise duration 472.61 +/- 112.49 sec and anginal episodes per week (1.33 +/- 1.18) was not significantly different (p less than 0.05) when compared to conventional isosorbide dinitrate (exercise duration 468.33 +/- 135.28 sec and anginal episodes per week 1.55 +/- 104). Twice a day long acting sustained release isosorbide dinitrate is as effective as four times a day conventional short acting isosorbide dinitrate. Such a regimen is likely to lead to a better patient compliance and ease of antianginal therapy.

Adult↗