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PubMedDate not supplied

The cytoprotective effect of a nitric oxide donor drug on gastric mucous membrane of rats treated with ketoprofen, a non-steroidal anti-inflammatory drug.

BACKGROUND: Non-steroidal anti-inflammatory drugs are considered today a very important group of medication, with a wide variety of therapeutic use, in different areas of modern medicine. Despite their beneficial effects on the patient, these drugs show a high incidence of side effects, mainly in the gastrointestinal tract. The physiopathological mechanisms of non-steroidal anti-inflammatory drugs induced lesions and the gastric mucosa defense mechanism became an important source for medical research, especially those which try to evaluate the role of nitric oxide as a cytoprotective agent. AIM: To define a possible cytoprotective effect of a nitric oxide donor, isosorbide dinitrate, on the gastric mucous of rats submitted to non-steroidal anti-inflammatory drugs ketoprofen treatment. METHODS: Adult male Wistar rats, previously submitted to starvation for 24 hours and divided in three groups: group I (standard): animals that received isotonic saline solution intragastric by gavage and intravenous. Group II (control-ketoprofen): animals that received isotonic saline solution intragastric by gavage and ketoprofen intravenous. Group III (nitrate/ketoprofen): animals that received 2mM solution of isosorbide dinitrate intragastric by gavage and ketoprofen intravenous. Later on, these animals were sacrificed and had their stomach removed and submitted to macroscopical, microscopical and biochemical studies. The evaluated parameters were: a) gastric lesion index; b) gastric mucous layer thickness; c) gastric tissue nitrate/nitrite (NOx) concentration and d) gastric tissue malondialdehyde concentration. RESULTS: a) Gastric lesion index evaluation showed a smaller statistically significant incidence on the animals of group III; b) group III showed a thicker mucous layer, which also was statistically significant, when compared to group II; c) the variation on tissue nitrate/nitrite concentration was similar in all three groups, without statistical significance when compared to each other. CONCLUSION: Isosorbide dinitrate has a cytoprotective activity on the gastric mucosa of rats submitted to ketoprofen action.

Animals↗
PubMedDate not supplied

Nitrates in the elderly. Pharmacological considerations.

Although a significant proportion of patients receiving nitrates are elderly, surprisingly little published work is available describing the pharmacokinetics and pharmacodynamics of these agents in elderly patients. The lack of pharmacokinetic data is related to the difficulty in assaying nitrates and there are at present no definitive data describing the effect of aging on their bioavailability or elimination. A common finding in old age is of decreased hepatic first-pass metabolism. This would affect isosorbide-2-mononitrate and isosorbide-5-mononitrate less than isosorbide dinitrate and nitroglycerin (glyceryl trinitrate). Venous responsiveness to nitrates does not appear to alter with age, so that pharmacodynamic properties would not be expected to alter. However, decreased baroreflex function causes an increased tendency for posturally related side effects to occur. Mechanisms of tolerance are likely to be unaltered but any possible alteration in quantitative aspects of tolerance has not been studied. Nitrate therapy in the elderly would benefit from systematic investigation. At the moment, therapy needs to be titrated to the individual patient, with care taken to avoid age-related side effects by careful initiation of therapy and appropriate reviews of each patient.

Absorption↗
PubMed1987

Historical aspects of nitrate therapy.

The exciting story of the development of nitrates as drugs in clinical medicine is briefly reviewed. Glyceryl trinitrate (nitroglycerin) was synthesised by Sombrero in 1847. Amyl nitrite was discovered a few years later and was used by Guthrie in 1859. The first report on the action of glyceryl trinitrate and amyl nitrite was published by Brunton in 1867, and further papers were published by Murell in 1879. Organic nitrates appeared in the 1930s. Krantz and co-workers synthesised and used mannide dinitrate, which was longer acting than the nitrates that had been used previously. Research on a similar drug, isosorbide dinitrate, was initiated by Porjé in Stockholm. The drug was first marketed in Sweden in 1946. Isosorbide dinitrate was independently synthesised in the United States by Harris and colleagues in the 1950s. The drug was used fairly extensively on both sides of the Atlantic. However, there was a temporary decrease in popularity around 1970 when Needleman and colleages reported oral nitrates to be of questionable value, as they underwent rapid biotransformation during first-pass metabolism in the liver. This opinion was later altered and today the drug enjoys worldwide acceptance in different formulations. Also, in recent years one of the active metabolites, isosorbide 5-mononitrate, has been marketed as an effective antianginal drug.

Cardiovascular Diseases↗
PubMed1987

Determination of nitrates in plasma.

Because of the high efficacy of existing nitrates, alternative dosage formulations have been developed rather than new compounds. These new formulations challenge the analyst to develop analytical methods with lower sensitivity and higher precision. Isosorbide dinitrate is analysed in the presence of its major metabolites isosorbide 2-mononitrate and isosorbide 5-mononitrate. The present method is an improvement over previously published methods. It is not possible to analyse glyceryl trinitrate and its major metabolites 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate with the necessary sensitivity in one chromatogram. A 2-step procedure is therefore applied. The extraction procedures, the gas chromatographic conditions, imprecision and inaccuracy of the methods, the lower limits of quantitation, sample chromatograms and applications of all methods are described in detail. Thus, the possibilities of modern analytical methods in the determination of nitrates in the lower picogram region are demonstrated.

Biotransformation↗
PubMed1987

Glyceryl trinitrate (nitroglycerin) and the organic nitrates. Choosing the method of administration.

Nitrate usage worldwide is on the increase as the indications for therapy expand. Present indications for nitrate therapy include chronic stable angina pectoris, unstable angina pectoris, complications of acute myocardial infarction, and 'unloading' therapy for acute and chronic congestive heart failure. Nitrates are also being used in the operating suite by anaesthesiologists to control systolic blood pressure during various surgical procedures. New nitrate delivery systems have recently become available which provide considerable dosing flexibility, further increasing the interest in this group of compounds. The dominant action of nitrates is a direct effect on vascular smooth muscle, producing vasodilation of the veins and arteries. These drugs decrease myocardial work by lowering systolic blood pressure, systemic vascular resistance, and reducing intracardiac dimensions. In addition, nitrates have a potent effect on cardiac preload as a result of systemic venodilatation. There is also some evidence that nitrates exert direct effects on the coronary circulation (vasodilatation of coronary arteries and coronary collateral vessels, and direct atherosclerotic stenosis dilatation). These actions may play a role in relieving myocardial ischaemia. Adverse sequelae of nitrate therapy are well known and serious adverse reactions are uncommon. Headache and dizziness are the most frequent side effects. Nitrate tolerance is a definite problem - present evidence indicates that long acting formulations, high doses, or frequent dosing regimens are particularly likely to induce vascular tolerance to nitrates. Consequently, provision of a nitrate-free interval has taken on increasing significance as a strategy to avoid tolerance. Nitrate delivery systems are numerous. Although availability varies from country to country, in most countries there are a wide variety of formulations of glyceryl trinitrate (nitroglycerin) available, including sublingual and oral tablets, oral spray, topical ointment as well as discs or patches for transdermal administration, a transmucosal tablet and an intravenous formulation. Similar formulations of isosorbide dinitrate, except buccal tablets, are available in some countries. Isosorbide 5-mononitrate, a potent metabolite of isosorbide dinitrate, is achieving increasing popularity as an antianginal drug. Optimum nitrate therapy requires a good understanding of the properties of the various formulations, particularly onset and duration of action and propensity to induce tolerance.(ABSTRACT TRUNCATED AT 400 WORDS)

Angina Pectoris↗
PubMed1994

Vasodilators in heart failure. Conclusions from V-HeFT II and rationale for V-HeFT III.

The Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT I and II) provided information about heart failure treated with conventional therapy, and evaluated the long term efficacy of vasodilators. In V-HeFT I, the combination of hydralazine and isosorbide dinitrate provided a beneficial effect on prognosis in heart failure. V-HeFT II demonstrated that enalapril had a more favourable effect on 2-year survival than a combination of hydralazine plus isosorbide dinitrate. However, the hydralazine-isosorbide dinitrate combination exerted the most favourable short term impact on exercise performance and left ventricular ejection fraction. The V-HeFT studies showed that, although not all vasodilators are alike, their differing effects might be beneficial when used in combination. Determination of the potential additive effect of the calcium antagonist felodipine, a vasodilator, when used in combination with an ACE inhibitor, is the major goal of V-HeFT III.

Clinical Trials as Topic↗
PubMed1999

Effect of inhaled nitric oxide on gas exchange in patients with congestive heart failure. A randomized, controlled trial.

BACKGROUND: Conventional vasodilators increase ventilation-perfusion mismatch and do not improve gas exchange even though they reduce pulmonary hypertension. However, the effects of nitric oxide inhalation on ventilatory and gas exchange values in patients with congestive heart failure are not known. OBJECTIVE: To investigate the effect of nitric oxide inhalation on gas exchange in patients with congestive heart failure. DESIGN: Randomized, controlled trial. SETTING: University hospital. PATIENTS: 16 patients with congestive heart failure (New York Heart Association class II or III). INTERVENTIONS: Patients inhaled nitric oxide gas at graded concentrations (n = 8) or were given intravenous isosorbide dinitrate, 2.5 mg (n = 8). MEASUREMENTS: Hemodynamic and ventilatory variables and blood gases were measured 5 minutes after inhalation of different doses of nitric oxide and 10 minutes after administration of isosorbide dinitrate. RESULTS: Nitric oxide inhalation reduced the mean pulmonary arterial pressure in a dose-dependent manner without altering the mean arterial pressure or cardiac output. At a dose of 40 parts per million, nitric oxide inhalation increased PaO2 (change from baseline, 12.0 mm Hg [95% CI, 2.3 to 21.7 mm Hg]; P = 0.014) and decreased the alveolar-arterial difference in partial pressure of oxygen (change, -8.6 mm Hg [CI, -16.8 to -0.4 mm Hg]; P = 0.038) and the ventilatory equivalent for carbon dioxide output (change, -6.7 [CI, -10.3 to -3.1]; P < 0.001). Although isosorbide dinitrate similarly decreased pulmonary arterial pressure, it did not alter gas exchange or ventilatory variables. CONCLUSIONS: Because nitric oxide inhalation improved gas exchange, it may be used as a supportive therapy when other conventional vasodilators worsen gas exchange.

Administration, Inhalation↗
PubMed1976

Combination vasodilator therapy for severe chronic congestive heart failure.

A patient with severe, chronic congestive heart failure was unresponsive not only to conventional therapy, but also to nonparenteral nitroglycerin and isosorbide dinitrate; he became nitroprusside dependent. Oral minoxidil therapy produced a significant decrease in systemic vascular resistance and an increase in cardiac output, with no tachycardia, hypotension, or decrease in systemic and pulmonary venous pressures. The addition of sublingual isosorbide dinitrate decreased venous pressures and produced a further increase in cardiac output. The combination of oral minoxidil and sublingual isosorbide dinitrate maintained clinical and hemodynamic improvements, and the patient could be weaned off nitroprusside. Deterioration in hemodynamics occurred with the withdrawal of minoxidil. Therapy with oral hydralazine produced hemodynamic effects comparable to those of oral minoxidil. These observations suggest that chronic reduction of impedance to left ventricular ejection with minoxidil or hydralazine is possible in patients with severe intractable heart failure and deserves further clinical trial.

Chronic Disease↗
PubMed2003

[Clinical study on "sini" decoction in treating stenocardia for coronary heart disease].

OBJECTIVE: To observe clinical effect of "Sini" decoction on stenocardia for coronary heart disease. METHODS: 63 cases of stenocardia for coronary heart disease with deficiency of yang or cold syndrome were randomly divided into "Sini" decoction group (therapeutic group, 35 cases) and isosorbide dinitrate group (contrast group, 28 cases). Drug effects of the two groups were compared by clinical symptoms, electrocardiogram (ECG), myocardial oxygen consumption and cardiac function. RESULTS: Similar to isosorbide dinitrate, "Sini" decoction could improve clinical symptoms and ECG, decrease frequency of stenocardia and dose of nitroglycerin on stenocardia for coronary heart disease. But "Sini" decoction had better effects on reducing myocardial oxygen consumption and improving cardiac funrtion than isosorbide dinitrate. CONCLUSION: "Sini" decoction can treat stenocardia for coronary heart disease with deficiency of yang or cold syndrome.

Adult↗
PubMedDate not supplied

[Correction of hemodynamic disorders in phthisiologic surgical patients with chronic pulmonary heart disease in preoperative period].

The hypokinetic blood circulation was detected in 49% (from a total of 180) patients with different forms of pulmonary tuberculosis. Obvious initial signs of disorders in the function of the cardio-vascular system were diagnosed in one half of patients with the normal kinetic blood circulation. 48 patients underwent a preoperative treatment to correct the hemodynamic disorders. Isosorbide dinitrate (5 mg/day), verapamilhydrochlorid (240 mg/day), maleate enalapril (5 mg/day) and isosorbide dinirate (80 mg/day) were administered simultaneously. The preoperative preparation of patients lasted from 4 to 7 days. The cardiac beat, and the mechanical index of the functioning of the left ventricle essentially improved, while the total peripheral resistance significantly decreased due to all treatment schemes. Isosorbide dinitrate and verapamilhydrochlorid produced the most effect on the parameters of the central hemodynamics. The administration of all above preoperative preparation schemes in patients with pulmonary tuberculosis reduces the operation-anesthesiology risk.

Drug Therapy, Combination↗
PubMed2003

[Results of international study of quality of life of patients with stable angina treated with nitrates (IQOLAN)].

Effect of transition from multiple administration of short acting nitrates to once daily use of isosorbide-5-mononitrate on angina class and quality of life was studied in 280 patients with stable angina pectoris. Transition to isosorbide-5-mononitrate was associated with increases of (in units) exercise tolerance (Delta=-6.6+/-0.35, p<0.001), satisfaction from treatment (Delta=-2.1+/-0.12, p<0.001), degree of psychological discomfort (Delta=-2.8+/-0.21, p<0.001), decreases of numbers of attacks of angina (Delta=-4.0+/-0.22, p<0.001) and side effects (Delta=-4.1+/-0.29, p<0.001), increase of average distance of walking without chest pain or dyspnea (from 372.1+/-415.1 to 586+/-663.5 m), shortening of duration of episodes of angina (from 4.7+/-4.0 to 4.1+/-7.2 min), significant lowering of angina class (p<0.0001). Thus in patients with ischemic heart disease long acting formulation of isosorbide-5-mononitrate provided rapid onset and stability of therapeutic action what eventually resulted in effective prevention of attacks of angina and improvement of quality of life.

Angina Pectoris↗
PubMed1999

[Anti-angina treatment in stable forms of angina pectoris with emphasis on nitrates].

Current evidence strongly suggests that coronary atherosclerosis is a common denominator in patients with stable effort angina pectoris. The concept of pathophysiology of coronary atherosclerosis is presented--angiographic and pathologic evidence now suggest presence of eccentric and irregular atherosclerotic lesions (sometimes associated with plaque rupture) and simultaneously present endothelial dysfunction increases sensitivity of vascular smooth muscles to physical and biochemical stimuli with propensity to spasm. Ischemia is due to an increased myocardial oxygen demand (increased heart rate or blood pressure) that cannot be met because of fixed coronary reserve. The organic nitrates are important drugs for the treatment of patients wit angina. The mechanism(s) of their action is presented--biotransformation and liberation of nitric oxide which stimulates guanylyl cyclase and conversion of GTP (by guanylyl cyclase) to cGMP, which causes vasodilatation but reduces platelet adhesion and aggregation too. Sublingual nitroglycerin and isosorbide dinitrate are effective in the treatment of acute episodes of angina. Long-acting nitrate preparations are effectiveness include intermittent transdermal nitroglycerin, standard formulation and sustained-release isosorbid dinitrate (but better isosorbid-5-mononitrate because of longer duration of action of action and no 1st pass hepatic metabolism) (nitrate-free interval should be of 8-10 hours duration). The place of the therapy with betablockers and calcium channel blockers in angina pectoris is presented as well and their combination with nitrates.

Angina Pectoris↗
PubMed1990

[Effect of nitrates on left ventricular function and exercise tolerance in patients with mild circulatory failure caused by ischemic heart disease].

In 26 patients with ischaemic heart disease with symptoms of mild chronic circulatory failure (NYHA grade II) aged 56.2 +/- 14.4 years the left ventricular function was tested by two-dimensional echocardiography, the exercise tolerance was determined on cycle ergometer at submaximal workloads, the cardiothoracic index (CTI) and cardiac volume index (CVI) were calculated from chest radiograms. The tests were done before and after 2 and 6 weeks of treatment with isosorbide dinitrate in doses of 49.6 +/- 15.2 mg/day. Isosorbide was found to increase somewhat the ejection fraction (EF), and to raise statistically significantly (p less than 0.05) the velocity of shortening of the circumferential fibres in left ventricular myocardium (mVCF), and to reduce the internal dimensions of the left ventricle (LVIDd and LVIDs), without changing the values of the ejection index (SVI) and cardiac index (CI). Decreased transverse dimensions of the left ventricle was correlated with a significant decrease of the CVI index. No statistically significant effect of isosorbide was noted on the parameters characterizing exercise tolerance but the quotient of the exercise-induced heart rate by the workload (HR/Wat) and the index of myocardial oxygen requirement (HRx Ps) were decreased in a demonstrable way.

Adult↗
PubMed1989

[Dose-response behavior and long-term effect of organic nitrates. Experimental and clinical studies].

The effect of isosorbide dinitrate (ISDN) in patients with stable angina pectoris consists of an effect on the capacity vessels, of an increase in the arterial compliance (wind kessel function), a dilation of reactive stenoses in the coronary system, an improvement in the collateral function and a direct myocardial effect. In practice isosorbide dinitrate should be given preferably in single doses of 20 mg or more in a non-depot form for maintenance therapy; oral administration three or four times a day is appropriate. The dose effect relation justifies a dose increase in individual cases. Taking the galenics and therapy intervals into consideration, an anti-anginal effect can be seen in acute as well as chronic treatment. With chronic administration of the substance a weakening of the haemodynamic effects occurs. This does not necessarily interfere with the anti-ischemic effect. This weakening can best be explained by counter-regulatory processes. With the usual nitrate doses a tolerance on the vasculary level is not reached, i.e. an alteration in molecular processes. On the other hand, under conditions, under which the weakening of haemodynamic effects becomes fully visible, as for example in ergometric exercise with elevated legs, a decrease in the antianginal efficacy can be observed during a maintenance therapy with isosorbide dinitrate.

Angina Pectoris↗
PubMed1989

In vivo actions of organic nitrates on platelet function in humans.

Nitroglycerin and isosorbide dinitrate (ISDN), the most commonly used nitrate vasodilators, have been shown to possess antiplatelet properties. It has also been shown, interestingly, that their inhibition of aggregation (mostly upon ADP and adrenaline) occurs in vivo at concentrations 1-2 log orders lower than in vitro, and in the full therapeutic range. Many different hypotheses may explain such an in vivo/in vitro difference: 1) that nitrates induce prostacyclin synthesis; 2) that they synergize prostacyclin; 3) that they give rise to more active in vivo metabolites; 4) that some other requirement for their action, such as the availability of reducing thiols, may be a limiting factor in the in vitro setting. The discrimination among such hypotheses should contribute new insights into nitrate action at the platelet level. On the basis of experiments on cultured endothelial cells and vascular fragments, we had previously concluded against prostacyclin induction by nitrates. On the other hand, ISDN may decrease the IC50 for prostacyclin in aggregation by suprathreshold doses of various aggregating agents, and therefore, be synergistic with this endogenous antiplatelet substance. Compared to ISDN, the two longer-lived metabolites isosorbide-2- and isosorbide-5-mononitrates (IS-2-MN, IS-5-MN) appear remarkably different in terms of antiplatelet potency in vitro (minimum effective concentrations 10(-7)-10(-6)M for IS-2-MN, 10(-4)M for IS-5-MN, for ADP-and adrenaline-induced aggregation and thromboxane (TX) B2 production).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationship, Drug↗
PubMed1989

[The effect of molsidomine on bicycle ergometry in patients with stable angina pectoris].

The authors investigated the effect of a single dose of 4 mg molsidomine on the course of bicycle ergometry. This effect was compared with that of 120 mg isosorbide dinitrate retard and with placebo. Isosorbide dinitrate in this large dose significantly protracted the period before angina pectoris developed after exercise, it significantly reduced the duration of stenocardias, significantly increased the total work output, significantly prolonged the period before a reduction of the ST segment occurred on the ECG and significantly reduced the values of reduction of the ST segments. Moisidomine in medium doses significantly protracted the period before angina pectoris developed after exercise and significantly increased the total work output. After comparison of the described results with those of investigations where smaller doses of isosorbide dinitrate were used, the authors assume that after increasing the dose of molsidomine its effect will be comparable with large nitrate doses.

Adult↗
PubMed1986

[Intraindividual dose-response relationship of sustained-release Elantan].

Fifteen patients with coronary artery disease and stable angina pectoris were included in a double-blind, randomized, cross-over study. The patients received 25, 50 and 100 mg isosorbide-5-mononitrate, as well as a placebo, for subsequent one week periods. On the 7th day of each treatment period, 8 h after medication, an exercise test was performed. A highly significant (p less than 0.001) and dose-dependent reduction of the sum of the ST-segment depression was observed at similar work loads: 28.6%, 46% and 63.5% decreases occurred with the 25, 50 and 100 mg isosorbide-5-mononitrate doses, respectively. Compared to placebo, the frequency of anginal attacks and the consumption of nitroglycerin also decreased highly significantly (p less than 0.001) with all three doses. Isosorbide-5-mononitrate plasma levels (8 h post-application) increased linearly with the dose; amounting to 228 +/- 53, 485 +/- 93 and 991 +/- 177 ng/ml at the 25, 50 and 100 mg doses of the sustained-release medication forms, respectively.

Aged↗