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PubMed1984

Differences in the production of methemoglobin during high-dose treatment with isosorbide dinitrate or isosorbide 5-mononitrate.

12 patients with coronary heart disease were studied to see whether high doses of isosorbide dinitrate (ISDN, Corovliss) or isosorbide 5-mononitrate (IS-5-MN, Ismo) increase the erythrocyte methemoglobin production in an acute experiment and after 4 days of medication. The patients were divided into two groups. Group 1 (6 patients) was given a single dose of 80 mg ISDN on the morning of day 1 and Group 2 (6 patients) was given 80 mg IS-5-MN as a single oral dose. Under the influence of the IS-5-MN no change was observed from the initial methemoglobin (met-Hb) value (0.81% of the total Hb) at measurements performed 1 and 2 h after the administration of the drug. In Group 1 (ISDN) the initial met-Hb value was 0.58% of the total Hb, a slight increase to 0.70% being observed after 1 h and to 0.77% after 2 h (p less than 0.05). The patients were then treated as follows for a further 4 days: Group 1 480 mg ISDN/d, Group 2 480 mg IS-5-MN/d. On day 5 the initial met-Hb values in both groups were unchanged compared to day 1. The patients were then given first 80 mg ISDN (Group 1) or 80 mg IS-5-MN (Group 2) and 4 h later a single dose of 160 mg of the appropriate substance. In Group 2 (IS-5-MN) the met-Hb content remained unaffected. In Group 1 a slight increase of the met-Hb to 0.79% occurred 1 h after 80 mg ISDN and to 0.9% after 2 h (p less than 0.05). The dose of 160 mg ISDN gave rise to a further slight increase to 1.00% (after 1 h) and 1.13% (after 2 h) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Absorption and excretion of isosorbide dinitrate and isosorbide-2-mononitrate in dogs.

In a crossover design four male dogs were given orally or i.v. [14C]isosorbide dinitrate (ISDN) or [14C]isosorbide-2-mononitrate (2-ISMN) at a dose of 1 mg kg-1 (70-80 microCi). Virtually all of the oral dose was absorbed and all of the radioactivity was excreted in the urine. The profile of serum radioactivity was similar after all drug administrations. ISDN was rapidly denitrated, giving rise to isosorbide-5-mononitrate (5-ISMN) as a major metabolite, and 2-ISMN as a minor metabolite. The apparent elimination half-life from serum of 2-ISMN and 5-ISMN was 2-3 h. More than 50% of the serum radioactivity after [14C]2-ISMN was due to unchanged drug. The apparent volume of distribution of 2-ISMN averaged 8.3 litres. The results show that, in contrast to ISDN, administration of 2-ISMN resulted in relatively high unchanged drug levels in the serum; the disposition of radioactivity after [14C]ISMN was however similar to that after [14C]ISDN. The findings support the concept that the concentrations of ISDN, 2-ISMN and 5-ISMN in the blood are inversely related to the rates of denitration, and that the vascular activity of the nitrates of isosorbide relates to the rates of their dinitration.

Absorption↗
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↗
PubMed1983

Oral absorption and disposition of isosorbide dinitrate and isosorbide mononitrates in man.

The plasma concentrations of isosorbide dinitrate (ISDN) and its two pharmacologically active metabolites isosorbide 2-mononitrate (IS-2-MN) and isosorbide 5-mononitrate (IS-5-MN) were determined after oral administration of 20 mg ISDN and 20 mg of each of the mononitrates. The mean concentration-time curve of ISDN showed a peak of 51.6 ng/ml 15 min after drug intake, and declined bi-exponentially with a terminal half-life of 36.5 min. The mean concentrations of the simultaneously measured metabolic products IS-2-MN and IS-5-MN reached a maximum of 40.5 ng/ml and 144.4 ng/ml, respectively. In contrast, after the direct ingestion of isosorbide mononitrates, peaks of 409.1 ng/ml (IS-2-MN) and 483.2 ng/ml (IS-5-MN) were observed in the corresponding mean curves. Mean half-lives of 1.72 h for IS-2-MN and 4.20 h for IS-5-MN were calculated. The mean apparent volumes of distribution were 44.5 l (IS-2-MN) and 34.4 l (IS-5-MN), suggesting that the isosorbide mononitrates are distributed throughout the whole body fluid. After ISDN administration, it was estimated that 3.0 mg IS-2-MN and 7.8 mg IS-5-MN reached the systemic circulation. This corresponds to 63% of the ISDN dose being converted to isosorbide mononitrates by metabolic processes.

Administration, Oral↗
PubMed1984

Differences in the nitrite ion formation and the toxicological findings between isosorbide dinitrate and isosorbide-5-mononitrate.

In the metabolism of isosorbide dinitrate (ISDN), fast denitration with the formation of nitrite ions and a mononitrate plays an important role. In contrast, the denitration of isosorbide-5-mononitrate (IS-5-MN) to isosorbide is very slow. Accordingly po administration of high doses of ISDN (92.5 and 236 mg/kg) in conscious dogs led to maximum nitrite concentrations in the blood of 0.9 and 3.3 mg/liter, respectively. In contrast, with equimolar doses of IS-5-MN (75 and 191 mg/kg) we were able to detect nitrite ions reliably only at the higher dose and this gave a maximum blood concentration of 0.4 mg/liter. The rise in nitrite ion concentration is followed by the formation of methemoglobin. As is known from the literature, there is a rise in the activity of alkaline phosphatase in the serum of rabbits in addition to methemoglobin formation following repeated administration of sodium nitrite. So we have specifically investigated whether this is also the case following ISDN and IS-5-MN administration. On po administration of 236 mg/kg ISDN/day to dogs, there was a continuous rise in alkaline phosphatase from about the 20th day onward which we did not observe after the equimolar dose of IS-5-MN (191 mg/kg). NaNO2, 35 mg/kg po, led to a comparable maximal rise in methemoglobin to that obtained with 236 mg/kg ISDN. Repeated po administration of 35 mg/kg NaNO2/day also caused a rise in alkaline phosphatase. It is concluded that the formation of nitrite ions from ISDN is the reason for the rise in methemoglobin and alkaline phosphatase. The lower formation of nitrite ions from IS-5-MN can also be of clinical importance, at least in certain cases.

Alkaline Phosphatase↗
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↗
PubMed1982

[Long-term percutaneous therapy of angina pectoris with isosorbide dinitrate with reference to isosorbide dinitrate blood levels].

The efficiency of percutane isosorbide dinitrate (ISDN) therapy on 61 subjects with coronary heart diseases (angina pectoris, postinfarction state and myocardial insufficiency) was examined. Serum levels of ISDN in 12 subjects were measured gaschromatographically. The haemodynamic and clinical parameters received, as well as, the reduced attack-note of stenocardic symptoms demonstrate the therapeutic and prophylactic effectiveness of this kind of therapy. Sufficient systemic availability of ISDN in organism was evident. Non of these subjects seem to develop a tolerance, because stenocardic symptoms were not obvious. No diminished sensitivity to acute acting nitrates was present. Intervals in long-term therapy with nitrates are discussed. "Isoket ointment" comes in premeasured doses and is easy to apply. Good patient compliance is obtained.

Aged↗
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↗
PubMed2000

[Comparison of dinitrate isosorbide retard forms in ischemic heart disease patients with stable effort angina].

AIM: To compare antianginal and anti-ischemic efficiency and tolerance of two forms of isosorbide dinitrate--cardiket-retard 120 mg and cardiket-retard 40 mg in IHD patients with stable effort angina. MATERIAL AND METHODS: The study included 18 IHD patients with stable angina of functional class II (5 patients) and III (13 patients). The trial was open cross-over. The treatment with both the forms lasted 1 month. Frequency of anginal attacks and exercise tolerance by veloergometry data were assessed. RESULTS: A significant decrease in the number of anginal attacks and greater exercise tolerance was recorded in cardiket 120 mg intake once a day. Both forms were well tolerated, serious side effects were absent. CONCLUSION: Comparison of the two isosorbide dinitrate dosage forms--cardiket 120 mg once a day and cardiket 40 mg 3 times a day--showed that the former is superior by clinical efficiency.

Adult↗
PubMed1982

[Absorption of isosorbide dinitrate in guinea-pig intestine and in the colon of sheep (author's transl)].

Segments of the intestine of anaesthetized guinea-pigs and the colon of conscious sheep were perfused with saline containing 0.1--25 mg/l 1,4:3,6-dianhydrosorbitol-2,5-dinitrate (isosorbide dinitrate, ISDN). The increase in ISDN uptake was linearly related to its concentration. Absorption was rapid. In the jejunum and the ileum of guinea-pig, 7% of perfused ISDN was absorbed per 10 cm of intestine in the proximal and 15% in the distal colon, respectively. In the total colon of sheep, 83% disappeared during the perfusion. Per unit of length, surface or dry weight of mucosa the net flux of ISDN in the small intestine was only half that in the colon. Absorption from the colon per unit of wet weight of the gut was only slightly higher compared to the small intestine. 1 h after the infusion of 14C-labelled ISDN into the large intestine of sheep filled with normal contents 14C-activity was detected in the plasma, a maximum was reached after 4 h. Renal excretion of ISDN or its 14C-labelled metabolites was parallel to the ISDN concentration in blood. Microbial degradation of ISDN to CO2 in colon contents was insignificant.

Animals↗
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↗
PubMed1982

Plasma concentrations of isosorbide dinitrate and mononitrates after acute and chronic oral administration of isosorbide dinitrate in man.

Isosorbide dinitrate (Cedocard) was given orally to patients in doses of either 5, 20 or 40 mg t.i.d. for 19 days, and the plasma concentrations of unchanged product and of its mononitrates were measured. While the concentration of isosorbide 2-mononitrate remained stable, the concentration of isosorbide dinitrate and of isosorbide 5-mononitrate in plasma increased gradually during the first days of administration. Decrease in presystemic or systemic clearance is probably responsible for this phenomenon.

Administration, Oral↗