A Double-Blind Cross-Over Study on the Effectiveness and Possible Development of Tolerance during Long-Term Therapy with Isosorbide-5-Mononitrate or Isosorbide Dinitrate Slow-Release in Coronary Artery Disease

Rennhak, U.; Riebesel, T.; Biamino, Giancarlo

doi:10.1007/978-3-642-70234-1_19

Cited by 25 publications

(7 citation statements)

References 7 publications

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“…Bearing in mind that plasma concentrations did not exceed 500 ng/ml and that the suggested tolerance level of around 300 ng/ml was not exceeded for too long [5], there is quite a good explanation for the absence of development of nitrate tolerance, which can lead to a loss of antiischemic and antianginal efficacy.…”

Section: Discussionmentioning

confidence: 96%

Anti-ischemic and antianginal effects of 60 mg isosorbide-5-mononitrate in patients treated chronically after myocardial infarction

Wrobel¹

1990

Eur J Clin Pharmacol

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25 patients with stable angina pectoris after acute myocardial infarction were given single and maintenance doses of isosorbide-5-mononitrate (IS-5-MN) in a controlled-release formulation. For evaluation of the efficacy of this treatment, a score based on exercise tests and patient's complaints including additional antianginal medication were used 4 weeks after the acute event. For assessment of anti-ischemic effect non-invasive parameters including heart rate, arterial blood pressure, changes in ST segments, frequency of premature ventricular beats and systolic time intervals were used before medication, 5 h after the initial dose and 7 days after maintenance therapy. The therapeutic concept of interval treatment was found to be effective. Nitrate tolerance did not develop. Measurements of plasma levels under steady-state conditions revealed minimum values of 100 ng/ml and maximum levels of 460 ng/ml which is in between the threshold for anti-ischemic effect and development of nitrate tolerance, respectively.

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Section: Discussionmentioning

confidence: 96%

Anti-ischemic and antianginal effects of 60 mg isosorbide-5-mononitrate in patients treated chronically after myocardial infarction

Wrobel¹

1990

Eur J Clin Pharmacol

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“…In fact, the antianginal efficacy of IS 5-MN during long term treatment of stable angina was docu mented in a multicentre clinical trial, where two thirds of the patients were successfully controlled under 20 mg b.i.d. regimen [13]; another controlled study by Rennhak et al [14] confirmed that IS 5-MN, twice a day, was capable of significantly reducing the STsegment depression following ergometric test.…”

Section: Discussionmentioning

confidence: 99%

Oral Isosorbide 5-Mononitrate Can Protect from Myocardial Ischemia Induced by Ergonovine Test and by Isometric Effort

Distante¹,

Lombardi²,

Moscarelli³

et al. 1987

Cardiology

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Isosorbide 5-mononitrate (IS 5-MN) has favourable pharmacodynamic properties, such as the specific half-life (close to 5 h) and the bioavailability (100% after oral ingestion). The efficacy of IS 5-MN (20 mg t.i.d.) in the treatment of stable angina has been documented in previous studies. In the present acute study, two subsets of patients were evaluated: the first group consisted of 10 patients with coronary vasospasm in whom oral IS 5-MN was effective in preventing myocardial ischaemia due to an abrupt reduction in coronary blood flow; the second group regarded 8 patients with a mixed form of angina, where the responsible mechanism for ischaemia can be considered a combination of increased myocardial oxygen demand and reduction of coronary blood flow due to vasoconstriction of large vessels. In all these patients, IS 5-MN was able to protect against transient myocardial ischaemia induced by isometric test. In conclusion, from the data available in our studies, IS 5-MN appears to be a useful drug in anginal patients: the beneficial effect is likely based on its capability both to prevent the abnormal vasoconstriction of diseased coronary vessels and to reduce myocardial oxygen demand.

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“…In eight studies involving 189 patients, IS-5-MN was at least as effective as ISDN or transdermal GTN (59,66,67,81,87), and definitely more active than sustained release preparations of ISDN (50,60,75).…”

Section: Comparative Studies Of Is-5-mn and Other Antianginal Drugsmentioning

confidence: 98%

Isosorbide‐5‐mononitrate

Barrett

McConnell

Melikian

et al. 1988

Cardiovascular Drug Reviews

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In 1967 Dietz ( 19) reported that isosorbide dinitrate (ISDN), a long-acting antianginal drug, was rapidly metabolized to isosorbide-5-mononitrate (IS-5-MN, Fig. 1 ), isosorbide-2-mononitrate (IS-2-MN), and isosorbide. Studies from the early 1970s established that although ISDN and IS-5-MN were radically different in terms of drug disposition (68), they were remarkably similar in their pharmacological effects (90). Unlike ISDN, IS-5-MN was not subject to first-pass degradation, and thus the mononitrate persisted in plasma for many hours after ISDN had disappeared (68). Most importantly, IS-5-MN and ISDN are similar in that both are effective dilators of the coronary and systemic vasculature (90). It is now widely appreciated that IS-5-MN is the molecule responsible for the sustained antianginal actions of ISDN. This monograph is a review of the studies that have led to this understanding and to the subsequent development of IS-5-MN as a clinically important antianginal compound. CHEMISTRYThe chemical structure of IS-5-MN is shown in Fig. 1. Chemically, it is 1,4:3,6-dianhydro-D-glucitol 5-nitrate. The nitrate ester in the 5-position of IS-5-MN exists in the endo-configuration. This provides a degree of steric protection from denitration. The chemically similar drug ISDN has nitrate ester groups in both the 2-and 5-positions. Because the nitrate ester in the 2-position is in the exo-configuration, it is not stencally protected. Therefore, it is more susceptible to metabolic attack than the nitrate ester group in the 5-position. The steric hindrance protecting the 5-nitrate is responsible for the long half-life of IS-5-MN.IS-5-MN is an odorless, white, fine, crystalline powder with a slightly sweet taste; it is freely soluble in water, methanol, acetone, and ethanol. Its molecular weight is 19 I . 14, and its melting point range is 87"-90°C. Because of the potentially explosive nature of pure IS-5-MN, it is supplied as a tnturation with lactose. PRECLINICAL PHARMACOLOGY Effects in Experimental Models of Myocardial IschemiaExperimental production of canine ischemia by coronary artery occlusion and treadmill exercise closely simulates exercise-induced angina pectoris. The severity of

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A Double-Blind Cross-Over Study on the Effectiveness and Possible Development of Tolerance during Long-Term Therapy with Isosorbide-5-Mononitrate or Isosorbide Dinitrate Slow-Release in Coronary Artery Disease

Cited by 25 publications

References 7 publications

Anti-ischemic and antianginal effects of 60 mg isosorbide-5-mononitrate in patients treated chronically after myocardial infarction

Anti-ischemic and antianginal effects of 60 mg isosorbide-5-mononitrate in patients treated chronically after myocardial infarction

Oral Isosorbide 5-Mononitrate Can Protect from Myocardial Ischemia Induced by Ergonovine Test and by Isometric Effort

Isosorbide‐5‐mononitrate

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