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At least 1,513 records · Page 84Linked to original sources
PubMed1988

Organic nitrates: direct antiplatelet effects and synergism with prostacyclin. Antiplatelet effects of organic nitrates.

Isosorbide dinitrate inhibits platelet function in vivo at concentrations about 10 times lower than in vitro (10(-7)-10(-6) vs. 10(-6)-10(-5) M). We investigated two possible reasons for this difference. Isosorbide dinitrate and its in vivo longer-lived metabolites, isosorbide-2- and isosorbide-5-mononitrate were incubated for 5 min with human platelet-rich plasma or washed platelets; irreversible aggregation was induced with threshold doses of ADP, adrenaline, collagen, arachidonic acid and thrombin, and thromboxane (TX) B2 production was measured by radioimmunoassay. Moreover, the concentration of exogenous prostacyclin required to inhibit platelet aggregation by 50% (IC50) after preincubation with isosorbide dinitrate or vehicle was determined. At 10(-7) M, only isosorbide-2-mononitrate inhibited aggregation (-12%, p less than 0.05) and TX production (-36%, p less than 0.01) by ADP. At 10(-6) M isosorbide-2-mononitrate inhibited aggregation by adrenaline more than the dinitrate (-41% vs. -25%, p less than 0.05). In addition, at supra-threshold doses of all the aggregating agents, isosorbide dinitrate decreased IC50 of prostacyclin from 2.7 +/- 1.2 to 0.36 +/- 0.2 nM. Generation of a platelet-active metabolite and synergism with prostacyclin are new properties of isosorbide dinitrate that may account for antiplatelet effects in vivo.

Adult↗
PubMed1995

Which drug to choose for stable angina pectoris: a comparative study between bisoprolol and nitrates.

The choice between beta-blockade or nitrates as first line treatment for stable angina pectoris is based upon the different mechanisms of action and patient characteristics. We performed a clinical trial comparing the efficacy of the longacting beta-blocker bisoprolol once daily and the short acting nitrate, isosorbide dinitrate, three times daily in the reduction of anginal complaints in daily life and under stress. Thirty patients were enrolled in a double-blind randomised cross-over study. Both bisoprolol and isosorbide dinitrate were effective in reducing anginal attacks and nitroglycerin consumption significantly, but bisoprolol was significantly more effective than isosorbide dinitrate. Bisoprolol improved the workload during bicycle exercise testing significantly, but the improvement with isosorbide dinitrate was not significant. Despite the reduction in maximal rate pressure product, bisoprolol was significantly (P < 0.05) more effective at improving total workload and reducing the time to onset of angina than isosorbide dinitrate. The rate pressure product did not change significantly with isosorbide dinitrate. In this study, bisoprolol 10 mg once daily was more effective and caused less side effects than isosorbide dinitrate 20 mg three times a day. It seems questionable if monotherapy of isosorbide dinitrate 20 mg t.i.d is an adequate drug regime for stable angina pectoris.

Adult↗
PubMed1998

Randomised trial of nitric oxide donor versus prostaglandin for cervical ripening before first-trimester termination of pregnancy.

BACKGROUND: Vaginal administration of the nitric oxide donor isosorbide mononitrate can induce effective ripening of the human cervix. We investigated whether this drug is associated with fewer side-effects than prostaglandins when used to ripen the cervix before first-trimester surgical termination of pregnancy, and assessed whether the extent of cervical ripening it induces is clinically sufficient. METHODS: 66 primigravid women scheduled for surgical termination were assigned to receive before surgery, per vaginam, isosorbide mononitrate 40 mg or 80 mg, or the prostaglandin analogue gemeprost 1 mg. The primary measured outcome was onset of new symptoms before termination of pregnancy. FINDINGS: More women remained symptom-free after isosorbide mononitrate than after gemeprost (28/44 [64%] vs 3/22 [14%], p<0.005). Pretreatment with gemeprost resulted in abdominal pain in 73% of women and vaginal bleeding in 32% compared with 3% and 0%, respectively, after isosorbide mononitrate, whereas, more women developed headache after isosorbide mononitrate (27%) than after gemeprost (0%). Cervical resistance and measured intraoperative blood loss were lowest after pretreatment with gemeprost. The measured cervical resistance and intraoperative blood loss with either dose of isosorbide mononitrate did not differ from those in a comparison group of 22 parous women not in the randomised trial. INTERPRETATION: Pretreatment with isosorbide mononitrate to ripen the cervix before first-trimester termination of pregnancy is associated with fewer side-effects than gemeprost treatment and adequately decreases cervical resistance. Isosorbide mononitrate could be used as an alternative to gemeprost for this indication.

Abortifacient Agents, Nonsteroidal↗
PubMedDate not supplied

Clinical pharmacokinetics of organic nitrates.

Plasma concentrations of glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide 2- and 5-mononitrates in man have been measured after administration via different routes. Appropriate precautions have to be taken in the administration of these agents (to avoid loss during intravenous infusion), and in their sampling and assay. Pharmacokinetic calculations based on plasma concentrations should be viewed with caution, as the data on which these calculations are based are often very limited, and the very rapid disappearance of for example glyceryl trinitrate from plasma makes the choice of an appropriate kinetic model and exact calculations difficult. Glyceryl trinitrate disappears from plasma within a few minutes, and a high apparent volume of distribution and a very high systemic clearance are found. After oral administration, plasma concentrations are very low; with sublingual or cutaneous administration, higher plasma concentrations can be obtained, suggesting a high first-pass extraction after oral administration, but quantitative data on bioavailability are lacking. For isosorbide dinitrate the systemic clearance, although high, is lower than for glyceryl trinitrate; disappearance from the plasma is slower and plasma concentrations after different routes of administration are much higher. Here too, quantitative data on bioavailability are lacking. High plasma concentrations of isosorbide 2-mononitrate and isosorbide 5-mononitrate are found in plasma after administration of isosorbide dinitrate. These metabolites have a good bioavailability, and half-lives of around 2.5 hours for isosorbide 2-mononitrate and 5 hours for isosorbide 5-mononitrate. Only very limited data are available about the influence of disease states and interactions with food and other drugs on the kinetics of the organic nitrates. It is very difficult to correlate the effects of the nitrates to their plasma concentrations; counter-regulation, development of tolerance, and the presence of metabolites could disturb the interpretation of such a relationship. It is at present impossible to predict the pharmacological effects or the efficacy of organic nitrates on the basis of their plasma concentrations.

Administration, Oral↗
PubMed1995

[The noninvasive identification of patients with angina and normal coronary arteries].

BACKGROUND: Although patients with syndrome X (angina and normal coronary arteries, in absence of coronary spasm, cardiomyopathy or valvulopathy) and those with stable angina as well as documented coronary artery disease share a similar clinical presentation (effort related symptoms, positive exercise stress testing and reversible perfusion defects), their prognosis is markedly different. Coronary atherosclerosis is usually progressive relative to morbidity and mortality. Conversely prognosis both in terms of persistence of pain and mortality appears to be benign in syndrome X. Most cardiologists favor proceeding with coronary angiography in all patients presenting with exercise induced ST depression and reversible perfusion defects. However, it should not be assumed that this strategy will remain the preferred one. The aim of this study was to assess whether non invasive testing could identify underlying coronary artery anatomy, thus prognosis in the above subset of patients. The approach was selected on a clearly stated objective of how isosorbide dinitrate and verapamil may influence coronary flow reserve, thus exercise stress testing in syndrome X. Nitrates have been shown to reduce coronary flow reserve during stress tachycardia. The opposite occurs with calcium blockers. METHODS: We studied 48 patients with effort angina referred to our laboratory for diagnostic evaluation. All patients underwent two separate sessions at one-day interval. Each session consisted of exercise stress testing before and after isosorbide dinitrate (s.l.; 5-10 mg) or verapamil (i.v.; 10 mg), given in a randomized crossover fashion. Angiography was performed within 3 months from testing. Efficacy of drugs in terms of exercise capacity was assessed by using the following criteria: 1) prevention of significant (> or = 0.1 mV) ST depression while reaching same workload levels attained during baseline testing; 2) improvement in the ischemic thresholds, that is an increase in: time to 0.1 mV ST depression > or = 120 sec., with heart rate (> or = 10 bpm) and rate pressure product (> or = 2 U x 1000) greater than those attained during baseline testing; 3) increase in time to peak exercise (> or = 120 sec). RESULTS: In syndrome X, both drugs resulted ineffective in one patient, one patient showed a favourable response to isosorbide dinitrate whereas the remaining 13/15 patients improved exercise capacity following verapamil, but not isosorbide dinitrate. The opposite occurred in coronary artery disease patients: both isosorbide dinitrate and verapamil were effective in 21/33 patients, and ineffective in 8/33 patients. The remaining 4 patients responded to isosorbide dinitrate but not to verapamil. CONCLUSIONS: 1) Verapamil, but not isosorbide dinitrate, improves exercise capacity in syndrome X; 2) this does not apply to patients with stable angina; 3) a favourable response to verapamil but not to isosorbide dinitrate is both a sensitive (86%) and specific (100%) method for identifying patients with angina and normal coronary arteries; 4) non invasive testing may select those effort angina patients who have to proceed directly to coronary angiography; 5) some patients with effort related angina may not require further investigation.

Adult↗
PubMed1986

Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Clinical Trials as Topic↗
PubMed1987

Medical treatment of patients with severe exertional and rest angina: double blind comparison of beta blocker, calcium antagonist, and nitrate.

The role of medical treatment of patients who had resting nocturnal angina as well as exertional angina was investigate. The effects of atenolol 100 mg a day, nifedipine 20 mg three times a day, and isosorbide mononitrate 40 mg twice a day were investigated in a double blind, triple dummy randomised study. Nine patients with coronary artery disease, early positive exercise tests, and transient daytime and nocturnal ambulatory ST segment changes were initially assessed off all antianginal medication. They were then treated with each drug for three five day periods. Angina diaries were reviewed and maximal treadmill exercise tests and 48 hour ambulatory ST segment monitoring were performed at the end of each treatment period. Resting and exercise heart rate and blood pressure were significantly lower on atenolol than on either isosorbide mononitrate or nifedipine. The duration of exercise to 1 mm ST segment depression was significantly greater on atenolol than on isosorbide mononitrate. Only one patient had an improvement in exercise tolerance on nifedipine that was greater than the improvement on atenolol; this patient had single vessel disease. The total number and duration of episodes of ST segment change during ambulatory monitoring were significantly lower with atenolol than on either isosorbide mononitrate or nifedipine. Nocturnal ST segment changes were abolished in six patients on atenolol, in six patients on nifedipine, and in five patients on isosorbide mononitrate. When nocturnal ST segment changes occurred, their frequency was reduced with all three drugs. Pain was abolished in four patients on atenolol and pain relief was significantly better on atenolol than on isosorbide mononitrate. There was no significant difference in pain relief between isosorbide mononitrate and nifedipine. Thus beta receptor blockade with atenolol was the most effective means of reducing myocardial ischaemia both during exercise and at rest at night without causing deterioration in any patient. Nocturnal myocardial ischaemia in patients with severe coronary artery disease can be effectively treated with beta receptor antagonists and vasodilators.

Aged↗
PubMed1976

Vasodilator therapy for chronic left ventricular failure.

The effects of chronic oral vasodilator therapy were studied in a group of patients with refractory congestive heart failure. Fifteen patients were treated acutely with intravenous sodium nitroprusside and sublingual isosorbide dinitrate. After continuous therapy with nitroprusside and isosorbide dinitrate for up to 72 hours the patients were then placed on isosorbide dinitrate and oral phenoxybenzamine. Hemodynamic responses to nitroprusside, isosorbide dinitrate, and phenoxybenzamine with isosorbide dinitrate were determined. After a mean follow-up of seven months, nine patients who were receiving isosorbide dinitrate and phenoxybenzamine underwent repeat hemodynamic studies. Beneficial effects of acute vasodilator therapy included a significant reduction in pulmonary capillary wedge pressure and systemic vascular resistance, and significant increases in cardiac index and stroke work index. Mean arterial blood pressure and heart rate were unchanged. During the period of chronic vasodilator administration, no other change in basic therapy with isosorbide dinitrate and phenoxybenzamine (3-21 months), the favorable effects observed acutely were maintained. All patients demonstrated symptomatic improvement with minimal side effects. The beneficial hemodynamic responses that are noted with acute vasodilator therapy in patients in advanced congestive heart failure are maintained with oral therapy on a chronic basis.

Adult↗
PubMed1997

Differential effects of captopril and nitrates on muscle sympathetic nerve activity in volunteers.

BACKGROUND: The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Activation of SNS plays an important role in the pathophysiology and the prognosis of cardiovascular diseases such as heart failure, acute coronary syndromes, arrhythmia, and possibly hypertension. Vasodilators such as adenosine and sodium nitroprusside are known to activate SNS via baroreflex mechanisms. Because vasodilators are widely used in the treatment of patients with cardiovascular diseases, the aim of the present study was to assess the influence of clinically used dosages of isosorbide dinitrate and captopril on sympathetic nerve activity at rest and during stimulatory maneuvers. METHODS AND RESULTS: Twenty-eight healthy volunteers were included in this double-blind placebo-controlled study, and muscle sympathetic nerve activity (MSA; with microelectrodes in the peroneal nerve), blood pressure, heart rate, and neurohumoral parameters were measured before and 90 minutes after the oral administration of 40 mg isosorbide dinitrate or 6.25 mg captopril. Furthermore, a 3-minute mental stress test and a cold pressor test were performed before and 90 minutes after drug administration. Resting MSA did not change after captopril and decreased compared with placebo (P < .05 versus placebo), whereas isosorbide dinitrate led to a marked increase in MSA (P < .05). Systolic blood pressure was reduced by isosorbide dinitrate (P < .05), whereas captopril decreased diastolic blood pressure (P < .05). The increases in MSA, blood pressure, and heart rate during mental stress were comparable before and after drug administration regardless of the medication. During cold pressor test, MSA and systolic and diastolic blood pressures increased to the same degree independent of treatment, but after isosorbide dinitrate, the increase in MSA seemed to be less pronounced. Heart rate did not change during cold stimulation. Plasma renin activity increased after captopril and isosorbide dinitrate (P < .05), whereas placebo had no effect. Endothelin-1 increased after placebo and isosorbide dinitrate (P < .05) but not after captopril. CONCLUSIONS: Thus, captopril suppressed MSA despite lowering of diastolic blood pressure but allowed normal adaptation of the SNS during mental or physical stress. In contrast, the nitrate strongly activated the SNS under baseline conditions. These findings demonstrate that vasodilators differentially interact with the SNS, which could be of importance in therapeutic strategies for the treatment of patients with cardiovascular diseases.

Adult↗